Targeting Signaling Pathways for the Treatment of Triple-Negative Breast Cancer: A Review of Bitter Herbs' Potential¹
靶向三阴性乳腺癌治疗的信号通路：Bitter Herbs 潜力研究进展 ¹

Zongao Wang, Minghui Zhang, Shaojun Liu, Min Liu^*
王宗高， 张明辉， 刘少军， 刘敏^*

Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
南京中医药大学附属苏州中医医院， 中国， 苏州

Abstract: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor-2. This type of cancer is notorious for its rapid proliferation, high recurrence and metastasis rates, as well as its resistance to hormonal, targeted, and conventional radiotherapies. Consequently, there is a pressing need to explore additional potential therapeutic targets. Herbal medicine, an abundant source for developing anticancer drugs, boasts multiple target anti-tumor effects. Multi-targeted therapeutic strategies have been proposed, focusing on specific molecules and signaling pathways expressed in TNBC, such as PI3K/Akt/mTOR, NF-κB, Wnt/β-catenin, among others. In this review, we discuss several bitter herbs and their bioactive ingredients, which target diverse pathways for the treatment of TNBC, with the aim of furnishing more opportunities for future therapeutic interventions.
摘要：三阴性乳腺癌 （TNBC） 是一种高度侵袭性的乳腺癌，其特征是缺乏雌激素受体、孕激素受体和人表皮生长因子-2。这种类型的癌症因其快速增殖、高复发率和转移率以及对激素、靶向和常规放疗的耐药性而臭名昭著。因此，迫切需要探索更多潜在的治疗靶点。草药是开发抗癌药物的丰富来源，具有多种靶点抗肿瘤作用。 已经提出了多靶点治疗策略，专注于 TNBC 中表达的特定分子和信号通路，例如 PI3K/Akt/mTOR、NF-κB、Wnt/β-catenin 等。在这篇综述中，我们讨论了几种针对 TNBC 治疗的不同途径的苦味草药及其生物活性成分，旨在为未来的治疗干预提供更多机会。

Keywords: triple-negative breast cancer; bitter herbs; signaling pathways; bioactive ingredients; bitter taste receptors
关键词：三阴性乳腺癌; 苦菜;信号通路;生物活性成分;苦味受体

Figure 1 Graphical abstract Bitter herbs exert their effects on triple-negative breast cancer (TNBC) by targeting various signaling pathways, which ultimately inhibit the proliferation, metastasis, immune evasion, and development of drug resistance in TNBC cells. PI3K, phosphoinositide 3-Kinase. Akt, protein kinase B. mTOR, mammalian target of rapamycin,. NF-κB, nuclear factor kappa-B.
图 1 图形摘要苦草通过靶向各种信号通路对三阴性乳腺癌 （TNBC） 发挥作用，最终抑制 TNBC 细胞的增殖、转移、免疫逃避和耐药性的发展。PI3K，磷酸肌醇 3-激酶。Akt，蛋白激酶 B. mTOR，雷帕霉素的哺乳动物靶标，.NF-κB，核因子 kappa-B。

Introduction
介绍

According to incomplete statistics from the American Cancer Society, as of 2021, the global incidence of female breast cancer stands at 11.7%, surpassing lung cancer and emerging as the most prevalent form of cancer worldwide. Furthermore, its mortality rate reaches a staggering 6.7%, with even higher figures anticipated in developing nations[1]. Breast cancer is also one of the most prevalent cancer in China, with its mortality rate ranking fifth among female cancers, posing a serious threat to women's lives and health[2]. TNBC is a highly aggressive subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her-2) expression. It constitutes 15-20% of all breast cancers[3]. Unlike other types of breast cancer, TNBC exhibits higher proliferative activity and immune infiltration[4], rendering it more susceptible to distant recurrent metastases and resulting in a higher mortality rate within five years[5]. The primary organs susceptible to metastasis include the liver, lungs, brain, and bone[6,7]. Patients with TNBC require meticulous detection and proactive treatment, particularly following distant recurrence and metastasis, which could rapidly deteriorate and potentially result in death. Given that TNBC is negative for all breast cancer markers, endocrine therapy and anti-Her-2 therapy are not feasible, resulting in a scarcity of specific treatment options currently available. TNBC demonstrates significant heterogeneity and can be categorized into distinct subtypes based on gene expression profiles: basal-like type 1 (BL1), basal-like type 2 (BL2), mesenchymal (M), and luminal androgen receptor (LAR)[8]. The progression of TNBC and its malignant behaviors is characterized by the aberrant activation of multiple signaling pathways, including the PI3K/Akt/mTOR and Wnt/β-catenin pathways, among others. Constant exploration of novel individualized therapeutic approaches is being conducted in response to the diverse molecular typologies and varying expression characteristics of TNBC, encompassing immunotherapy, targeted therapies, nutrient therapies, and non-coding RNA-based therapies. By molecular classification and tailored treatment of TNBC, the success rate of therapy can be enhanced, thereby offering more potent therapeutic strategies for patients with TNBC [9,10].
根据美国癌症协会的不完全统计，截至 2021 年，全球女性乳腺癌的发病率为 11.7%，超过肺癌，成为全球最普遍的癌症形式。此外，其死亡率达到惊人的 6.7%，预计发展中国家的死亡率会更高[1]。乳腺癌也是中国最常见的癌症之一，其死亡率在女性癌症中排名第五，对女性的生命健康构成严重威胁[2]。TNBC 是一种高度侵袭性的乳腺癌亚型，其特征是缺乏雌激素受体 （ER）、孕激素受体 （PR） 和人表皮生长因子受体 2 （Her-2） 表达。它占所有乳腺癌的 15-20%[3]。与其他类型的乳腺癌不同，TNBC 表现出更高的增殖活性和免疫浸润[4]，使其更容易受到远处复发转移的影响，并导致五年内的死亡率更高[5]。易转移的主要器官包括肝脏、肺、脑和骨骼[6,7]。TNBC 患者需要细致的检测和积极治疗，尤其是在远处复发和转移后，这可能会迅速恶化并可能导致死亡。鉴于 TNBC 对所有乳腺癌标志物均呈阴性，内分泌治疗和抗 Her-2 治疗不可行，导致目前可用的特定治疗方案稀缺。 TNBC 表现出显著的异质性，可根据基因表达谱分为不同的亚型：基底样 1 型 （BL1）、基底样 2 型 （BL2）、间充质 （M） 和管腔雄激素受体 （LAR）[8]。TNBC 的进展及其恶性行为的特征是多种信号通路的异常激活，包括 PI3K/Akt/mTOR 和 Wnt/β-catenin 通路等。针对 TNBC 的不同分子类型和不同的表达特征，正在不断探索新的个体化治疗方法，包括免疫疗法、靶向疗法、营养疗法和基于非编码 RNA 的疗法。通过对 TNBC 进行分子分类和定制治疗，可以提高治疗成功率，从而为 TNBC 患者提供更有效的治疗策略 [9,10]。

Herbs and natural medicine, as a crucial resource for the development of anticancer drugs[11], possess the advantages of convenience, cost-effectiveness, and minimal side effects. This is attributed to their diverse array of secondary metabolites with broad pharmacological actions that can simultaneously target multiple cellular mechanisms[12]. In the earliest records of Shennong's Herbal Classic, Chinese medicine is classified based on four Qi and five tastes. The four Qi include cold, hot, warm, and cool, while the five tastes consist of sourness, bitterness, sweetness, pungency, and saltiness. Each of these categories is distinct from the others and produces a wide variety of effects in the medicines. Since ancient times, bitter substances have been considered potentially harmful, and individuals typically exhibit resistance to these compounds. This may arise from the body's self-defence mechanism to prevent potentially dangerous and harmful substances from invading the body[13,14]. The use of bitter herbs in traditional medicine is attributed to their detoxification effects, as cancer is often caused by the accumulation of carcinogenic toxins. Thus, bitter herbs and substances not only aid in mitigating the assault of harmful compounds but also exhibit a unique role in the management of malignant tumour diseases. Recent studies have discovered that certain bitter herbs and their compounds, such as dandelion [15], turmeric[16], and Sophorae Flavescentis Radix[17], exhibit potent inhibitory effects on the proliferation, metastasis, and drug resistance of TNBC. Therefore, from the perspective of bitter herbs, this review paper examines the impact of select bitter herbs and their bioactive ingredients on autophagy and apoptosis induction through diverse signaling pathways to inhibit proliferation, invasion, and recurrence of TNBC cells. Additionally, it explores potential therapeutic targets for TNBC by focusing on bitter herbs and their intrinsic bioactive ingredients in order to develop personalized treatment strategies for different subtypes of TNBC patients.
草药和天然药物作为抗癌药物开发的重要资源[11]，具有方便、成本效益高、副作用小等优点。这归因于它们多样化的次生代谢物，具有广泛的药理作用，可以同时靶向多种细胞机制[12]。在神农《中医经》的最早记载中，中医是根据四气五味进行分类的。四气包括寒、热、温、凉，而五味包括酸、苦、甜、辣和咸。这些类别中的每一个都与其他类别不同，并在药物中产生各种各样的效果。自古以来，苦味物质就被认为具有潜在危害，个体通常对这些化合物表现出抵抗力。这可能是由于身体的自我防御机制防止潜在危险和有害物质侵入身体[13,14]。在传统医学中使用苦药是由于其解毒作用，因为癌症通常是由致癌毒素的积累引起的。因此，苦味草药和物质不仅有助于减轻有害化合物的攻击，而且在恶性肿瘤疾病的管理中也表现出独特的作用。最近的研究发现，某些苦草及其化合物，如蒲公英[15]、姜黄[16]和苦参[17]，对三阴性乳腺癌的增殖、转移和耐药性表现出有效的抑制作用。 因此，本文从苦菜的角度出发，研究了精选苦菜及其生物活性成分通过多种信号通路抑制 TNBC 细胞增殖、侵袭和复发对自噬和细胞凋亡诱导的影响。此外，它通过专注于苦草及其内在生物活性成分来探索 TNBC 的潜在治疗靶点，以便为不同亚型 TNBC 患者制定个性化治疗策略。

The active ingredients of bitter herbs target distinct signaling pathways for the management of TNBC ( Table1 )
苦味草药的活性成分针对不同的信号通路，用于治疗 TNBC （ 表1 ）

Table 1 The effects of active ingredients from bitter herbs on TNBC.
表 1 苦味草药活性成分对 TNBC 的影响。

VM, vasculogenic mimicry. Dvl, dishevelled. PTCH1, patched-1. SMO, Smoothened. Gli1. EMT, epithelial-mesenchymal transformation. CSC, cancer stem cell. Bcl-2, B-cell lymphoma-2. PGK, phosphoglycerate kinase. EGFR, epidermal growth factor receptor. R0S, reactive oxygen species. Bax, BCL2-associated X protein. MAPK, mitogen-activated protein kinase. p70S6K, Ribosomal protein S6 kinase beta-1. CDK, cyclin-dependent kinase. MMP, matrix metalloproteinase. LC3, microtubule-associated proteins light eIF2α, eukaryotic initiation factor 2α. ERK, extracellular signal-regulated kinase. Bcl-xL, B-cell lymphoma-XL. MEK, mitogen-activated extracellular signal-regulated kinase. IKKα, IκB kinase alpha. IκBα, inhibitor of NF-κB. XIAP, X-linked inhibitor of apoptosis protein. THOC1,THO complex 1. JNK, c-jun N-terminal kinase. GRP78, glucose regulated protein 78kD. PERK, proteinkinaseR—like ERkinase. ATF, activating transcription factor. CHOP, CCAAT/enhancer-binding protein homologous protein. COX-2, cyclooxygenase-2. PARP , poly ADP-ribose polymerase. TNFR2,tumor necrosis factor receptor 2. EZH2, enhancer of zeste homolog 2. Ras、c-Raf CHK1, checkpoint kinase 1. TPI1, triosephosphate isomerase 1. PDGF, platelet-derived growth factor. GPI, glucose-6-phosphate isomerase. Bip, immunoglobulin heavy chain binding protein.
VM，血管生成模拟。Dvl，衣衫褴褛。PTCH1，修补 1。SMO，平滑。Gli1.EMT，上皮-间充质转化。CSC，癌症干细胞。Bcl-2，B 细胞淋巴瘤-2。PGK，磷酸甘油酸激酶。EGFR，表皮生长因子受体。R0S， 活性氧。Bax，BCL2 相关 X 蛋白。MAPK，丝裂原活化蛋白激酶。p70S6K，核糖体蛋白 S6 激酶 β-1。CDK，细胞周期蛋白依赖性激酶。MMP，基质金属蛋白酶。LC3，微管相关蛋白轻 eIF2α，真核起始因子 2α。ERK，细胞外信号调节激酶。Bcl-xL，B 细胞淋巴瘤-XL。MEK，丝裂原激活的细胞外信号调节激酶。IKKα，IκB 激酶 α。IκBα，NF-κB 抑制剂。XIAP，细胞凋亡蛋白的 X 连锁抑制剂。THOC1，THO 复合物 1。JNK，c-jun N 末端激酶。GRP78，葡萄糖调节蛋白 78kD。PERK，蛋白激酶 R—like ERkinase。ATF，激活转录因子。CHOP，CCAAT/增强子结合蛋白同源蛋白。COX-2，环氧合酶-2。PARP ，聚 ADP-核糖聚合酶。TNFR2，肿瘤坏死因子受体 2。EZH2，zeste 同源物 2 的增强子。Ras、c-Raf CHK1，检查点激酶 1。TPI1，磷酸丙糖异构酶 1。PDGF，血小板衍生生长因子。GPI，葡萄糖-6-磷酸异构酶。Bip，免疫球蛋白重链结合蛋白。

PI3K/Akt/mTOR signaling pathway
PI3K/Akt/mTOR 信号通路

The PI3K/Akt/mTOR signaling pathway represents a pivotal intracellular signaling cascade in mammalian cells, governing crucial cellular processes such as cell proliferation, nutrient utilization, and energy homeostasis. The activation of Akt is the most prevalent pathway in cancer, regulating downstream protein expression such as cyclin A1, cyclin D1, Bax, and Bcl-2. Dysregulated activation of the mTOR signaling pathway can result in aberrant cellular metabolism, uncontrolled growth, and excessive proliferation, thereby facilitating the development of various malignant lesions[18]. Relevant evidence has been accumulating, indicating that the activation of this specific signaling pathway can potentially trigger the development of TNBC[19]. As a crucial regulatory target in autophagy regulation, mTOR also contributes significantly to the high proliferation, frequent recurrence and metastasis, as well as drug resistance of TNBC[20]. As an orchestrated mechanism of programmed cell death, autophagy exerts a direct pro-apoptotic effect on tumor cells, thereby positioning mTOR as a promising therapeutic target for TNBC intervention.
PI3K/Akt/mTOR 信号通路代表了哺乳动物细胞中关键的细胞内信号级联反应，控制着细胞增殖、营养利用和能量稳态等关键细胞过程。Akt 的激活是癌症中最普遍的通路，可调节下游蛋白表达，如细胞周期蛋白 A1、细胞周期蛋白 D1、Bax 和 Bcl-2。mTOR 信号通路的激活失调会导致细胞代谢异常、生长不受控制和过度增殖，从而促进各种恶性病变的发展[18].相关证据一直在积累，表明这种特异性信号通路的激活可能会触发 TNBC 的发展[19]。作为自噬调控的关键调控靶点，mTOR 还对 TNBC 的高增殖、频繁复发和转移以及耐药性有显著贡献[20]。作为程序性细胞死亡的精心编排的机制，自噬对肿瘤细胞产生直接的促凋亡作用，从而将 mTOR 定位为 TNBC 干预的有前途的治疗靶点。

Bruceine D, a compound found in the traditional Chinese medicine Bruceae Fructus, effectively downregulated the expression of PI3K and suppressed Akt activation, thereby impeding the survival and invasion capabilities of MDA-MB-231 cells. These findings suggest that Bruceine D exerts its anti-TNBC effects through inhibition of the PI3K/Akt pathway[21]. Curcumin, a plant-derived polyphenol isolated from turmeric, exerts its inhibitory effects on TNBC invasiveness and reversal of resistance to certain antivascular drugs by disrupting the formation of VM through modulation of the PI3K/Akt pathway[16]. Matrine in Sophorae Flavescentis Radix activates autophagy and promotes TNBC cells apoptosis by inhibiting the PI3K/Akt pathway[22]. Sophoraflavanone G, another Sophorae Flavescentis Radix extract, exerts inhibitory effects on proliferation and metastasis of TNBC cells by targeting the epidermal EGFR/PI3K/Akt signaling pathway[23]. Rubioncolin C, derived from Rubia yunnanensis Diels, exhibits dose-dependent inhibition of mTOR and Akt phosphorylation, thereby inducing autophagic cell death in MDA-MB-231 cells[24]. Luteolin, found in bitter herbs such as dandelion and chrysanthemum[25,26], has demonstrated the ability to inhibit proliferation of AR(+) TNBC through the Akt/mTOR pathway. Moreover, this pathway induces epigenetic modifications on H3K27 and H3K56, resulting in reduced expression of MMP-9 and subsequently mitigating TNBC metastasis[27]. The triterpene Lupinol, derived from traditional Chinese medicine such as frankincense[28], can induce autophagy through PI3K/mTOR pathway and inhibit TNBC proliferation; on the other hand, it can reduce epithelial-mesenchymal transformation (EMT) and inhibit TNBC metastasis through autophagy down-regulating Twist1[29]. The concern lies in the fact that protective autophagy confers resistance to chemotherapeutic drugs on tumour cells and facilitates the survival of drug-resistant cells[30]. In contrast to several aforementioned herbal medicines that inhibit this signaling pathway, Radix tetrastigma extract activates the PI3K/Akt/mTOR pathway, thereby suppressing autophagy and augmenting chemo-sensitivity of TNBC cells as an adjunctive therapy[31]. This will probably be a new strategy for targeting mTOR therapy in the future.
Bruceine D 是一种在中药 Bruceae Fructus 中发现的化合物，可有效下调 PI3K 的表达并抑制 Akt 激活，从而阻碍 MDA-MB-231 细胞的存活和侵袭能力。这些发现表明，Bruceine D 通过抑制 PI3K/Akt 通路发挥其抗 TNBC 作用[21]。姜黄素是一种从姜黄中分离的植物来源多酚，通过调节 PI3K/Akt 通路破坏 VM 的形成，对 TNBC 侵袭性和逆转对某些抗血管药物的耐药性发挥抑制作用[16]。苦参碱通过抑制 PI3K/Akt 通路激活自噬并促进 TNBC 细胞凋亡[22]。槐黄烷酮 G 是另一种苦参提取物，通过靶向表皮 EGFR/PI3K/Akt 信号通路对 TNBC 细胞的增殖和转移产生抑制作用[23]。来源于云南 红宝石的 Rubioncolin C 对 mTOR 和 Akt 磷酸化表现出剂量依赖性抑制，从而诱导 MDA-MB-231 细胞自噬细胞死亡[24]。木犀草素存在于蒲公英和菊花等苦草本植物中[25,26]，已被证明能够通过 Akt/mTOR 通路抑制 AR（+） TNBC 的增殖。此外，该通路诱导 H3K27 和 H3K56 的表观遗传修饰，导致 MMP-9 表达降低，从而减轻 TNBC 转移[27]。 三萜羽扇豆醇来源于乳香等中药[28]，可通过 PI3K/mTOR 通路诱导自噬并抑制 TNBC 增殖;另一方面，它可以通过自噬下调 Twist 来减少上皮-间质转化 （EMT） 并抑制 TNBC 转移1[29]。令人担忧的是，保护性自噬会赋予肿瘤细胞对化疗药物的耐药性，并促进耐药细胞的存活[30]。与上述几种抑制这种信号通路的草药相比，四柱头根提取物激活 PI3K/Akt/mTOR 通路，从而抑制自噬并增强 TNBC 细胞的化疗敏感性，作为辅助疗法[31]。这可能是未来靶向 mTOR 疗法的新策略。

Wnt/β-catenin signaling pathway
Wnt/β-catenin 信号通路

The Wnt/β-catenin signaling pathway plays a pivotal role in regulating cellular processes such as proliferation, migration, and differentiation. Aberrant activation of this pathway often results in uncontrolled cell growth and differentiation, ultimately leading to the development of cancer[32]. The activation of the Wnt signaling pathway is characterized by the nuclear translocation of β-catenin, which governs the expression of numerous downstream proto-oncogenes. It has been demonstrated that activation of the Wnt/β-catenin signaling pathway is evident in TNBC and correlates with its unfavorable prognosis[33].
Wnt/β-catenin 信号通路在调节细胞增殖、迁移和分化等过程中起关键作用。该通路的异常激活通常会导致细胞生长和分化不受控制，最终导致癌症的发展[32]。Wnt 信号通路的激活以 β-catenin 的核转位为特征，它控制着许多下游原癌基因的表达。已经证明，Wnt/β-catenin 信号通路的激活在 TNBC 中很明显，并且与其不良预后相关[33]。

After extracting and verifying the active components of Bupleuri Radix, it was discovered that Saikosaponin D exhibited a potent anti-proliferative effect on TNBC cell lines HCC1937 by inhibiting the Wnt/β-catenin signaling pathway[34]. Quercetin also extracted from Bupleuri Radix upregulated the expression of e-cadherin in MDA-MB-231 cells, suppressed the nuclear translocation of β-catenin, and downregulated its downstream oncogenes such as cyclin D1 and c-Myc, thereby inhibiting the proliferation and invasion of TNBC[35,36]. Echinacoside, derived from Echinacea angustifolia[37], effectively inhibits the proliferation and metastasis of MDA-MB-231 cells by dose-dependently downregulating key factors LRP6, Dvl, β-catenin in the Wnt/β-catenin signaling pathway. Consequently, Echinacoside demonstrates promising potential for blocking the development of TNBC both in vivo and in vitro[38]. Silibinin, a natural compound derived from milk thistle, exerts an inhibitory effect on the phosphorylation and expression of LRP6 in MDA-MB-231 cells, thereby effectively blocking the Wnt/β-catenin signaling pathway and exhibiting anti-TNBC activity[39]. Curcumin suppresses the expression of various constituents involved in the Wnt/β-catenin signaling pathway (including Dvl, β-catenin), thereby inducing apoptosis in MDA-MB-231 cells and exhibiting anti-TNBC effects[40]. Naringin, abundantly present in traditional Chinese medicines such as Rhizoma drynariae, Aurantii Fructus, and Citri reticulatae pericarpium[41–43]，exerts its anti-TNBC effect by significantly inhibiting the β-catenin signaling pathway while inducing a substantial increase in p21 expression and a concurrent decrease in survivin levels. This molecular mechanism promotes apoptosis and cell-cycle arrest in TNBC cells[44]. The alkaloid oxymatrine in Sophorae Flavescentis Radix can counteract the activating effect of bevacizumab on the Wnt/β-catenin pathway, mitigate the carcinogenic potential of bevacizumab, and augment its anticancer efficacy[17]. Triptolide significantly enhanced apoptosis in MDA-MB-231 cells and downregulated the expression of β-catenin, suggesting that triptolide may induce apoptosis in TNBC cells through modulation of the Wnt/β-catenin signaling pathway[45].
在提取和验证柴胡的活性成分后，发现柴胡皂苷 D 通过抑制 Wnt/β-catenin 信号通路对 TNBC 细胞系HCC1937表现出有效的抗增殖作用[34]。柴胡槲素还上调了 MDA-MB-231 细胞中 e-cadherin 的表达，抑制了 β-catenin 的核转位，并下调了其下游癌基因如细胞周期蛋白 D1 和 c-Myc，从而抑制了 TNBC 的增殖和侵袭[35,36]。紫锥菊苷来源于紫锥菊[37]，通过剂量依赖性下调 Wnt/β-catenin 信号通路中的关键因子 LRP6、Dvl β-catenin 有效抑制 MDA-MB-231 细胞的增殖和转移。因此，紫锥菊苷在体内和体外阻断 TNBC 的发展方面显示出有希望的潜力[38]。水飞蓟苷是一种来源于水飞草的天然化合物，对 MDA-MB-231 细胞中 LRP6 的磷酸化和表达起抑制作用，从而有效阻断 Wnt/β-catenin 信号通路并表现出抗 TNBC 活性[39]。姜黄素抑制参与 Wnt/β-catenin 信号通路的各种成分（包括 Dvl、β-catenin）的表达，从而诱导 MDA-MB-231 细胞凋亡并表现出抗 TNBC 作用[40]。 柚皮苷大量存在于传统中药中，如 Rhizoma drynariae、Aurantii Fructus 和 Citri reticulatae pericarpium[41–43]，通过显着抑制 β-catenin 信号通路发挥其抗 TNBC 作用，同时诱导 p21 表达的显着增加和存活素水平的降低。这种分子机制促进 TNBC 细胞凋亡和细胞周期停滞[44]。苦参中的生物碱氧化苦参碱可以抵消贝伐珠单抗对 Wnt/β-catenin 通路的激活作用，减轻贝伐珠单抗的致癌潜力，并增强其抗癌功效[17]。雷公藤内酯显著增强 MDA-MB-231 细胞凋亡并下调 β-catenin 的表达，表明雷公藤内酯可能通过调节 Wnt/β-catenin 信号通路诱导 TNBC 细胞凋亡[45]。

NF-κB signaling pathway
NF-κB 信号通路

The NF-κB signaling pathway is triggered by inflammatory and tumorigenic factors, thereby modulating the transcriptional regulation of key genes involved in various aspects of cancer development, including angiogenesis, apoptosis, and metastasis[46]. TNBC demonstrates heightened NF-κB activity in comparison to other subtypes of breast cancer[47]. In addition to the conventional activation pathway, this pathway intricately intersects with multiple cellular pathways, including the ERK and PI3K/Akt pathways, thereby exerting a multifaceted physiological role[48,49].
NF-κB 信号通路由炎症和致瘤因子触发，从而调节参与癌症发展各个方面的关键基因的转录调控，包括血管生成、细胞凋亡和转移[46]。与其他乳腺癌亚型相比，TNBC 表现出更高的 NF-κB 活性[47]。除了常规的激活途径外，该途径还与多种细胞途径错综复杂地相交，包括 ERK 和 PI3K/Akt 途径，从而发挥多方面的生理作用[48,49]。

The presence of genistein in Sophorae Tonkinensis Radix et Rhizoma was observed to inhibit NF-κB expression via the Notch-1/NF-κB pathway and MEK5/ERK5/NF-κB pathway, thereby suppressing MDA-MB-231 cells proliferation in TNBC cell lines[50–52]. Gypensapogenin H, derived from the traditional Chinese medicine Gynostemma pentaphyllum, exerts inhibitory effects on tumor growth and cell migration in TNBC by modulating the PI3K/Akt/NF-κB/MMP-9 signaling pathway[53]. Nobiletin, a component of the traditional Chinese medicine Citri reticulatae pericarpium, exerts anti-TNBC effects by suppressing NF-κB activation through the receptor tyrosinekinase-like orphan recepto (ROR)-IκBα/NF-κB signaling pathway[54]. Rugosin E derived from Rosa rugosa Thunb exerts inhibitory effects on MDA-MB-231 cells proliferation and induces apoptosis by suppressing the NF-κB signaling pathway and modulating the expression of its downstream effectors(including XIAP, Bcl-2, Bcl-xL, cyclin D1, c-Myc)[55]. Andrographolide, an extract derived from Andrographis paniculata, exhibits the potential to suppress recurrent metastasis of TNBC by abrogating the expression of CSCs in TNBC through modulation of the NF-κB-Thoc1 axis[56]. Moreover, ginsenoside Rg3 present in ginseng exerts regulatory control over the Bax/Bcl-2 expression by suppressing the activation of NF-κB signaling pathway, thereby augmenting the responsiveness of TNBC cells towards paclitaxel therapy and serving as a potential adjunctive therapeutic approach[57].
观察到槐 花青 木黄素中存在金雀异黄素通过 Notch-1/NF-κB 通路和 MEK5/ERK5/NF-κB 通路 抑制 NF-κB 表达，从而抑制 TNBC 细胞系中 MDA-MB-231 细胞增殖[50–52]。绞股蓝素 H 来源于中药绞股蓝，通过调节 PI3K/Akt/NF-κB/MMP-9 信号通路对 TNBC 中的肿瘤生长和细胞迁移产生抑制作用[53]。川陈皮素是中药 Citri reticulatae pericarpium 的一种成分，通过受体酪氨酸激酶样孤儿接收 （ROR）-IκBα/NF-κB 信号通路抑制 NF-κB 激活而发挥抗 TNBC 作用[54]。源自 Rosa rugosa Thunb 的 rugosin E 对 MDA-MB-231 细胞增殖产生抑制作用，并通过抑制 NF-κB 信号通路和调节其下游效应子（包括 XIAP、Bcl-2、Bcl-xL、cyclin D1、c-Myc）的表达诱导细胞凋亡[55]。穿心莲内酯是一种源自穿心莲的提取物，通过调节 NF-κB-Thoc1 轴消除 TNBC 中 CSCs 的表达，显示出抑制 TNBC 复发性转移的潜力[56]。此外，人参中存在的人参皂甙 Rg3 通过抑制 NF-κB 信号通路的激活对 Bax/Bcl-2 表达施加调节控制，从而增强 TNBC 细胞对紫杉醇治疗的反应性，并作为一种潜在的辅助治疗方法[57]。

Hedgehog signaling pathway
Hedgehog 信号通路

The Hedgehog signaling pathway plays a crucial role in embryonic development and primarily remains inhibited, being predominantly involved in partial tissue maintenance and repair. This signaling pathway has been demonstrated to play a crucial role in the pathogenesis, progression, angiogenesis, and metastasis of various malignant tumors, including basal cell carcinoma and medulloblastoma[58]. Likewise, this pathway exerts an impact on the development and metastasis of breast cancer [59].
Hedgehog 信号通路在胚胎发育中起着至关重要的作用，并且主要保持抑制状态，主要参与部分组织维护和修复。 该信号通路已被证明在包括基底细胞癌和髓母细胞瘤在内的各种恶性肿瘤的发病机制、进展、血管生成和转移中起关键作用[58]。同样，该途径对乳腺癌的发生和转移产生影响 [59]。

The expression of Gli1, Gli2, and PTCH1 in the Hedgehog signaling pathway was effectively attenuated by curcumin, resulting in the suppression of TNBC proliferation, inhibition of EMT progression, and abrogation of BCSCs characteristics[60]. Sinomenine, an isoquinoline alkaloid isolated from the traditional Chinese medicine Sinomenii Caulis[61], exhibits inhibitory effects on the NF-κB-mediated Sonic Hedgehog (SHh) signaling pathway and subsequently modulates the expression of MMP-2 and vimentin, thereby attenuating the likelihood of pulmonary metastasis in TNBC[62].
姜黄素有效减弱了 Hedgehog 信号通路中 Gli1 、 Gli2 和 PTCH1 的表达，从而抑制了 TNBC 增殖，抑制了 EMT 进展，消除了 BCSCs 特性[60]。青藤碱是一种从中药青藤中分离的异喹啉生物碱[61]，对 NF-κB 介导的 Sonic Hedgehog （SHh） 信号通路具有抑制作用，随后调节 MMP-2 和 vimentin 的表达，从而降低 TNBC 肺转移的可能性[62]。

JAK/STAT signaling pathway
JAK/STAT 信号通路

The JAK-STAT pathway represents a prominent signaling mechanism for diverse cytokines and growth factors, exerting its effects through the activation of STAT dimers that translocate into the nucleus to modulate downstream target gene expression. This intricate regulatory network plays pivotal roles in governing cellular processes encompassing proliferation, differentiation, apoptosis, and immunomodulation[63]. The overexpression of the STAT family has been demonstrated in breast cancer, particularly in subtypes exhibiting higher malignancy at advanced stages. Notably, STAT3 is closely associated with cell migration, invasion, and metastasis [64].
JAK-STAT 通路代表了多种细胞因子和生长因子的重要信号转导机制，通过激活易位到细胞核的 STAT 二聚体来调节下游靶基因表达，从而发挥其作用。这个错综复杂的调控网络在控制细胞过程（包括增殖、分化、凋亡和免疫调节）中起着关键作用[63]。STAT 家族的过表达已在乳腺癌中得到证实，尤其是在晚期表现出较高恶性肿瘤的亚型中。值得注意的是，STAT3 与细胞迁移、侵袭和转移密切相关 [64]。

According to reports, Farfarae Flos extract induces apoptosis in MDA-MB-231 cells by downregulating JAK phosphorylation and inhibiting nuclear translocation of STAT3, thereby impeding signaling pathways and suppressing the expression of downstream target genes (including Bcl-2, Cyclin D1, and COX-2)[65]. Silybin, an extract of milk thistle, and salidroside, a specific extract of Rhodiola rosea L., effectively suppress the phosphorylation of JAK2 and STAT3. Furthermore, they impede the nuclear translocation of STAT3 and its subsequent DNA binding activity, thereby inhibiting the activation of the JAK2/STAT3 pathway. As a result, these compounds hinder MMP-2 activation leading to inhibition of proliferation, migration, and invasion in TNBC cells[66,67]. Similar to the extracts mentioned above, elecampane extracts exhibited selective inhibition of STAT3 phosphorylation at tyrosine 705, thereby impeding cellular growth and inducing apoptosis in MDA-MB-231 cells. However, it is noteworthy that elecampane extracts did not exert any influence on STAT upstream kinases[68]. Additionally, the tumor microenvironment plays a pivotal role in disease progression. The development of malignant tumors often coincides with immune system failure, leading to immune evasion and facilitating cancer progression. Dandelion, an herb known for its anti-inflammatory and anti-tumor properties, and its extracts have the potential to inhibit immune evasion by suppressing the interleukin-10 (IL-10) /STAT3/programmed cell death 1 ligand 1(PD-L1) signaling pathway, thereby restraining the proliferation and migration of MDA-MB-231 cells[15].
据报道，Farfarae Flos 提取物通过下调 JAK 磷酸化和抑制 STAT3 的核转位来诱导 MDA-MB-231 细胞凋亡，从而阻碍信号通路并抑制下游靶基因（包括 Bcl-2、Cyclin D1 和 COX-2）的表达[65]。水飞蓟宾（水飞蓟草的提取物）和红景天苷（红景天的特定提取物）可有效抑制 JAK2 和 STAT3 的磷酸化。此外，它们阻碍 STAT3 的核转位及其随后的 DNA 结合活性，从而抑制 JAK2/STAT3 通路的激活。因此，这些化合物会阻碍 MMP-2 的激活，从而抑制 TNBC 细胞的增殖、迁移和侵袭[66,67]。与上述提取物类似，榄坎烷提取物在酪氨酸 705 位点表现出对 STAT3 磷酸化的选择性抑制，从而阻碍细胞生长并诱导 MDA-MB-231 细胞凋亡。 然而，值得注意的是，榄坎潘提取物对 STAT 上游激酶没有任何影响[68]。此外，肿瘤微环境在疾病进展中起着关键作用。恶性肿瘤的发展通常与免疫系统衰竭同时发生，导致免疫逃避并促进癌症进展。 蒲公英是一种以其抗炎和抗肿瘤特性而闻名的草药，其提取物有可能通过抑制白细胞介素-10 （IL-10） /STAT3/程序性细胞死亡 1 配体 1 （PD-L1） 信号通路来抑制免疫逃避，从而抑制 MDA-MB-231 细胞的增殖和迁移[15]。

MAPK signaling pathway
MAPK 信号通路

The MAPK pathway components represent a tertiary kinase model implicated in diverse cellular physiological and pathological processes, encompassing cell proliferation, differentiation, migration, and inflammation[69]. Relevant studies have revealed aberrant activation of this pathway in TNBC[70].
MAPK 通路组分代表一种三级激酶模型，涉及多种细胞生理和病理过程，包括细胞增殖、分化、迁移和炎症[69]。相关研究显示该通路在 TNBC 中异常激活[70]。

It has been found that Ginsenoside 20(S)-protopanaxadiol, a metabolite of ginseng, regulates the balance of MMPs/programmed cell death 1 ligand 1
已经发现人参的代谢物人参皂甙 20（S）-protopanaxadiol 调节 MMPs/程序性细胞死亡 1 配体 1 的平衡 (TIMPs
TIMP) and reverses EMT by inhibiting the activation of the
并通过抑制EGFR
EGFR （英语）-mediated MAPK signaling pathway, thereby suppressing the metastasis of TNBC
介导的 MAPK 信号通路，从而抑制 TNBC 的转移[71]. Similar to berberine in Coptidis Rhizoma, it reduces EGFR expression and inhibits the phosphorylation of its downstream signaling molecules MEK and ERK, thereby suppressing IL-8 transcription and attenuating the aggressiveness of TNBC
.与黄连根瘤中的小檗碱类似，它降低 EGFR 表达并抑制其下游信号分子 MEK 和 ERK 的磷酸化，从而抑制 IL-8 转录并减弱 TNBC 的侵袭性[72]. Scutellarin in Scutellariae Radix alleviates tumor-necrosis factor-α
.黄芩中的黄芩素减轻肿瘤坏死因子α (TNF-α)-induced vascular endothelial barrier dysfunction by mediating the TNFR2-ERK1/2-
-通过介导 TNFR2-ERK1/2- 诱导血管内皮屏障功能障碍EZH2
EZH2 系列 signaling pathway, thereby reducing TNBC metastasis
信号通路，从而减少 TNBC 转移[73]. Wogonoside exerts inhibitory effects on mTOR activity and induces autophagy by modulating ERK1/2 and p38 signaling pathways, thereby augmenting apoptosis in MDA-MB-231 cells and attenuating their invasive potential
.沃格诺苷对 mTOR 活性产生抑制作用，并通过调节 ERK1/2 和 p38 信号通路诱导自噬，从而增强 MDA-MB-231 细胞的凋亡并减弱其侵袭潜力[74]. The Chinese herbal formula Baipu Huang Granules (composed of pulsatilla, dandelion, Scutellariae Radix, and Phellodendron amurense Rupr), exerts its antiproliferative effects on TNBC cells by inhibiting the repair of DNA damage through the inhibition of
.中草药配方白谱黄颗粒（由白头翁、蒲公英、黄芩和黄柏组成）通过抑制 DNA 损伤的修复，对 TNBC 细胞发挥其抗增殖作用DDR
DDR （东德方案） and MAPK/ERK signaling pathways
和 MAPK/ERK 信号通路[75]. Atractylenolide I (AT-1), present in Chinese herbs Atractylodes Rhizoma, exerts inhibitory effects on the proliferation and metastasis of TNBC cells by suppressing ERK phosphorylation, downregulating Bcl2 and
.存在于中草药白术根瘤中的白术内酯 I （AT-1） 通过抑制 ERK 磷酸化、下调 Bcl2 和CDK1 expression, inducing cell cycle arrest, and promoting apoptosis. Furthermore, AT-1 modulates glycolysis/gluconeogenesis by downregulating TPI1 and GPI expression, thereby impeding tumor growth and proliferation
表达、诱导细胞周期停滞和促进细胞凋亡。此外，AT-1 通过下调 TPI1 和 GPI 表达来调节糖酵解/糖异生，从而阻碍肿瘤生长和增殖[76]. Overexpression of PDGF in the breast cancer cell line MDA-MB-231 can activate the MAPK and Akt signaling pathways, promoting cell growth and proliferation
.乳腺癌细胞系 MDA-MB-231 中过表达 PDGF 可激活 MAPK 和 Akt 信号通路，促进细胞生长和增殖[77]. The active compound Ampelopsin E derived from Dryobalanops was found to significantly suppress the invasive proliferation of MDA-MB-231 cells by
.发现来自 Dryobalanops 的活性化合物 Ampelopsin E 通过以下方式显着抑制 MDA-MB-231 细胞的侵袭性增殖inhibiting
抑制 invasion-related proteins such as
侵袭相关蛋白，例如PDGF and MMPs, suggesting a potential mechanism involving the targeting of the PDGF-MAPK signaling pathway
和 MMPs，表明一种涉及靶向 PDGF-MAPK 信号通路的潜在机制[78]. In contrast to the effects of several aforementioned compounds, treatment with
.与上述几种化合物的效果相反，使用sinomenine
青 藤 碱 in MDA-MB-231 cells resulted in increased expression levels of p-ERK, p-JNK, and p-38. The sustained overactivation of ERK1/2 could potentially induce cell cycle arrest and subsequently trigger apoptosis
在 MDA-MB-231 细胞中导致 p-ERK 、 p-JNK 和 p-38 的表达水平升高。ERK1/2 的持续过度激活可能会诱导细胞周期停滞并随后触发细胞凋亡[79]. Similarly, in TNBC characterized by heightened ERK signaling, the persistent activation of ERK1/2 induced by Chrysosplenol d from Artemisia annua may trigger recognition by the cell's tumor suppressor system, leading to apoptosis and autophagic cell death
.同样，在以 ERK 信号增强为特征的 TNBC 中，青蒿蒿脾醇 d 诱导的 ERK1/2 持续激活可能触发细胞肿瘤抑制系统的识别，导致细胞凋亡和自噬细胞死亡[80].

Endoplasmic reticulum stress
内质网应激

The ER, an essential organelle involved in protein synthesis, folding, and modification, triggers endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) as an adaptive survival mechanism. This protective response becomes a pro-tumorigenic factor when tumor cells are exposed to various stressful stimuli such as aberrant transcription and metabolism in cancer cells, drug-induced stimulation leading to the accumulation of misfolded or unfolded proteins, disruption of redox reactions balance, perturbation of calcium-ion homeostasis, and nutrient deprivation[81]. Activation of relevant ERS-related pathways has been associated with poor prognosis in TNBC. However, sustained or intense stimulation beyond the limits of cellular repair can induce autophagic death and apoptosis through the UPR[82]. Therefore, targeting ERS emerges as a promising therapeutic strategy for the management of TNBC.
内质网是参与蛋白质合成、折叠和修饰的重要细胞器，可触发内质网应激 （ERS） 并激活未折叠蛋白反应 （UPR） 作为适应性生存机制。当肿瘤细胞暴露于各种应激刺激时，这种保护性反应成为促肿瘤因子，例如癌细胞中的异常转录和代谢、药物诱导的刺激导致错误折叠或未折叠的蛋白质积累、氧化还原反应平衡的破坏、钙离子稳态的扰动和营养剥夺[81].相关 ERS 相关通路的激活与 TNBC 的不良预后相关。然而，超出细胞修复极限的持续或强烈刺激可通过 UPR 诱导自噬死亡和细胞凋亡[82]。因此，靶向 ERS 成为一种有前途的 TNBC 治疗策略。

The exposure of MDA-MB-231 cells to dandelion extract was found to activate three branches of ERS, leading to the induction of G2/M block and apoptosis. Notably, the downstream target of PERK, CHOP protein, emerged as a key contributor to ERS-induced cell death. Therefore, it can be inferred that the strong activation of the PERK/p-eIF2α/ATF4/CHOP axis in dandelion is partially responsible for inducing cell death through ERS[83]. Saxifragifolin D derived from Androsace umbellata and Ginsenoside Rh1 obtained from ginseng both elicit ERS through a ROS-dependent pathway, thereby promoting autophagy and apoptosis in MDA-MB-231 cells[84,85]. Triptolide induces caspase-dependent apoptosis in MDA-MB-231 cells by activating the ERK pathway through targeting the PERK/eIF2α/ERK axis[86].
发现 MDA-MB-231 细胞暴露于蒲公英提取物会激活 ERS 的三个分支，导致 G2/M 阻断和细胞凋亡的诱导。值得注意的是，PERK 的下游靶标 CHOP 蛋白成为 ERS 诱导的细胞死亡的关键因素。因此，可以推断蒲公英中 PERK/p-eIF2α/ATF4/CHOP 轴的强烈激活部分导致通过 ERS 诱导细胞死亡[83]。源自雄螨伞形的虎耳草素 D 和源自人参的人参皂苷 Rh1 均通过 ROS 依赖性途径引发 ER，从而促进 MDA-MB-231 细胞的自噬和细胞凋亡[84,85]。雷公藤内酯通过靶向 PERK/eIF2α/ERK 轴激活 ERK 通路，诱导 MDA-MB-231 细胞中 caspase 依赖性细胞凋亡[86]。

Association between bitter taste receptors and TNBC
苦味受体与 TNBC 的关系

Bitter taste receptor signaling
苦味受体信号传导

Taste signals from the human body are transmitted to the central brain through taste receptors expressed by type II taste receptor cells (TRCs) located in the taste buds of the tongue[87]. In recent years, it has been discovered that taste receptors are not solely confined to the tongue, but also present in extra-oral tissues including the airway, gastrointestinal tract, and mammary glands[88,89]. This extra-oral tissue expression often presents potential therapeutic targets for the treatment of diseases. Bitter taste receptors, belonging to the G protein-coupled family[90], possess dual signaling pathways (Fig. 2) [91–93].
来自人体的味觉信号通过位于舌蕾中的 II 型味觉受体细胞 （TRC） 表达的味觉受体传递到中枢脑[87]。近年来，人们发现味觉受体不仅限于舌头，还存在于口腔外组织，包括气道、胃肠道和乳腺[88,89]。这种口腔外组织表达通常为疾病治疗提供潜在的治疗靶点。苦味受体属于 G 蛋白偶联家族[90]，具有双信号通路（图 2）[91–93]。

Figure 2 Diagram illustrating the signaling pathway of T2Rs. The first the α-gustducin-PDE-cAMP pathway. When bitter agonists bind to T2Rs, it activates α-gustducin, thereby activating PDE, reducing the concentration of intracytoplasmic cAMP, relieving the inhibition of cAMP on ion channels, and increasing the concentration of intracellular Ca²⁺, thus causing membrane depolarization and neurotransmitter release. The second pathway, referred to as the β,γ-gustducin-PLCβ2-IP3 pathway, involves bitter agonists binding to T2Rs and activating β,γ-gustducin which further activates PLCβ2. PLCβ2 hydrolyzes PIP2 into DAG and IP3. IP3 then binds to class III inositol trisphosphate receptor (IP3R3) located on the ER membrane. This binding event leads to opening of IP3-gated Ca²⁺ channels on ER membranes causing release of stored Ca²⁺. Subsequently, this triggers activation of TRPM5, an intracellular transient sensing channel that induces depolarization of cells and stimulates cytoplasmic neurotransmitter release.T2Rs, bitter taste receptors. PDE, phosphodiesterase. cAMP, cyclic adenosine monophosphate. PLCβ2, phospholipase C β2. IP3, inositol trisphosphate. PIP2, phosphatidylinositol-4,5-bisphosphate. DAG, diacylglycerol. TRPM5, transient receptor potential melastatin 5.
图 2 T2R 信号通路示意图。 第一个是 α-gustducin-PDE-cAMP 通路。当苦味激动剂与 T2R 结合时，激活 α-gustducin，从而激活 PDE，降低胞浆内 cAMP 的浓度，解除 cAMP 对离子通道的抑制，增加细胞内 Ca²⁺ 的浓度，从而引起膜去极化和神经递质释放。 第二种途径称为 β，γ-gustducin-PLCβ2-IP3 途径，涉及与 T2R 结合的苦激动剂并激活 β，γ-gustducin，从而进一步激活 PLCβ2。PLCβ2 将 PIP2 水解成 DAG 和 IP3。然后 IP3 与位于 ER 膜上的 III 类肌醇三磷酸受体 （IP3R3） 结合。该结合事件导致 ER 膜上的 IP3 门控 Ca²⁺ 通道打开，导致储存的 Ca²⁺ 释放。 随后，这会触发 TRPM5 的激活，TRPM5 是一种细胞内瞬时感应通道，可诱导细胞去极化并刺激细胞质神经递质释放。T2R，苦味受体。PDE，磷酸二酯酶。cAMP，环磷酸腺苷。PLCβ2，磷脂酶 C β2。IP3，肌醇三磷酸。PIP2，磷脂酰肌醇-4,5-二磷酸。DAG，甘油二酯。TRPM5，瞬时受体电位美拉他汀 5。

Possibility of targeting T2Rs for the treatment of TNBC
靶向 T2R 治疗 TNBC 的可能性

The activation of the T2Rs leads to an elevation in cytoplasmic Ca²⁺ concentration. Ca²⁺ act as second messengers of intracellular signaling pathways and regulate various physiological and pathological processes of cells, including proliferation, metabolism, gene transcription. Through complex signaling cascades, Ca²⁺ play a crucial role in regulating cell survival and death, which is pivotal for tumorigenesis and metastasis[94]. Furthermore, it has been observed that alkaloids, glycosides, flavonoids, and other compounds exhibit promising anticancer properties by acting as T2Rs agonists[93]. Differential expression of T2Rs was observed in breast cancer, pancreatic cancer, and neuroblastoma[95]. In the TNBC cell lines MDA-MB-231, a distinctive pattern of T2R4 down-regulation and T2R14 up-regulation was observed compared to non-breast cancer cells. Furthermore, activation of T2R4 and T2R14 exhibited inhibitory effects on the proliferation and migration of TNBC [96,97]. The previously discussed treatment of TNBC with bitter herbs operates through simultaneous multi-targeting, such as dandelion and turmeric. Their potent active ingredients effectively target various pathways concurrently to inhibit the progression of TNBC. However, it remains unclear whether any specific bitter ingredient can partially target T2Rs to exert an anti-TNBC effect. Therefore, we investigated potential signaling axes by analyzing other signaling pathways that interact with the T2Rs pathway.
T2R 的激活导致细胞质 Ca²⁺ 浓度升高。 Ca²⁺ 作为细胞内信号通路的第二信使，调节细胞的各种生理和病理过程，包括增殖、代谢、基因转录。通过复杂的信号级联反应，Ca²⁺ 在调节细胞存活和死亡中发挥关键作用，这对肿瘤发生和转移至关重要[94]。此外，已经观察到生物碱、糖苷、类黄酮和其他化合物通过充当 T2Rs 激动剂表现出有希望的抗癌特性[93]。在乳腺癌、胰腺癌和神经母细胞瘤中观察到 T2R 的差异表达[95]。在 TNBC 细胞系的 MDA-MB-231 中，与非乳腺癌细胞相比，观察到 T2R4 下调和 T2R14 上调的独特模式。此外，T2R4 和 T2R14 的激活对 TNBC 的增殖和迁移表现出抑制作用 [96,97]。前面讨论的苦味草药治疗 TNBC 是通过同时多靶点（例如蒲公英和姜黄）进行的。它们的强效活性成分有效地同时针对各种途径，以抑制 TNBC 的进展。然而，目前尚不清楚任何特定的苦味成分是否可以部分靶向 T2R 以发挥抗 TNBC 作用。因此，我们通过分析与 T2Rs 通路相互作用的其他信号通路来研究潜在的信号转导轴。

Upon bitter agonists binding to T2Rs, it triggers the induction of IP3 to bind with IP3R located on the ER. Consequently, a substantial release of Ca
当苦激动剂与 T2R 结合时，它会触发 IP3 的诱导与位于 ER 上的 IP3R 结合。因此，Ca 的大幅释放²⁺ from the ER into the cytoplasm occurs, leading to intracellular
从 ER 进入细胞质，导致细胞内Ca
钙²⁺ imbalance. This disruption subsequently initiates a severe ERS, resulting in elevated levels of ATF6,
不平衡。这种破坏随后引发了严重的 ERS，导致 ATF6 水平升高，X-box binding protein 1
X-box 结合蛋白 1 (XBP1s
XBP1), p-eIF2α and CHOP proteins and ultimately inducing apoptosis
、p-eIF2α 和 CHOP 蛋白并最终诱导细胞凋亡[98–100]. This may explain the partial action of dandelion extract on T2Rs of TNBC cells, targeting the PERK/p-eIF2α/ATF4/CHOP axis of ERS to induce cell death in MDA-MB-231
.这可能解释了蒲公英提取物对 TNBC 细胞 T2R 的部分作用，靶向 ERS 的 PERK/p-eIF2α/ATF4/CHOP 轴，诱导 MDA-MB-231 细胞死亡[83]. Certain T2Rs receptors are expressed not only on the cellular membrane but also on the nuclear membrane of cells. Moreover, certain bitter agonists possess the capability to traverse the cell membrane and enter the cytoplasm, directly binding to T2Rs on the nuclear membrane and exerting their effects. It has been observed that HNSCC cells express T2Rs on both their cellular and nuclear membranes, and in the presence of bitter agonists, these receptors induce alterations in nuclear
.某些 T2Rs 受体不仅在细胞膜上表达，而且在细胞的核膜上表达。此外，某些苦味激动剂具有穿过细胞膜进入细胞质的能力，直接与核膜上的 T2R 结合并发挥其作用。已经观察到 HNSCC 细胞在其细胞膜和核膜上都表达 T2R，并且在苦激动剂存在下，这些受体诱导核改变Ca
钙²⁺ levels, mitochondrial depolarization, activation of caspase, and apoptosis
水平、线粒体去极化、半胱天冬酶激活和细胞凋亡[101]. The same phenomenon has also been observed in lung cancer cells, such as A549 cells.
.在肺癌细胞（例如 A549 细胞）中也观察到了相同的现象。The
这 influence of intracytoplasmic Ca
胞浆内 Ca 的影响²⁺ on the increase in nuclear Ca
关于核 Ca 的增加²⁺ has been investigated by various researchers
已被各种研究人员调查. Previous studies have revealed that as the intracytoplasmic concentration rises, some
.以前的研究表明，随着胞浆内浓度的增加，一些Ca
钙²⁺ are likely to diffuse from the cytoplasm to the nucleus through the nuclear pore, resulting in an elevation of Ca
可能通过核孔从细胞质扩散到细胞核，导致 Ca 升高²⁺ concentration within the nucleus. However, there may be a transient delay in this process
集中在细胞核内。但是，此过程可能存在暂时性延迟[102]. However, it has been proposed by others that there is also an expression of IP3R at the nuclear membrane, which serves as a direct regulator of Ca
.然而，其他人提出，在核膜处也有 IP3R 的表达，它作为 Ca 的直接调节剂²⁺ flow within the nucleus
细胞核内的流动[103]. Therefore, we postulate that these two effects may act synergistically to jointly regulate the influx of Ca
.因此，我们假设这两种作用可能协同作用，共同调节 Ca 的流入²⁺ into the cell.
进入牢房。Unfortunately, the characterization of this nuclear receptor in TNBC remains elusive; however, it holds promising potential as a prospective avenue for further research.
不幸的是，TNBC 中这种核受体的特征仍然难以捉摸;然而，它作为进一步研究的潜在途径具有广阔的潜力。 Additionally, the elevated intracytoplasmic concentration of Ca
此外，胞质内 Ca 浓度升高²⁺ is accompanied by an accelerated uptake of Ca
伴随着 Ca 的加速摄取²⁺ by mitochondria, potentially resulting in mitochondrial calcium overload and subsequent opening of the PTP and release of cytochrome c, thereby initiating mitochondria-dependent apoptosis
通过线粒体，可能导致线粒体钙过载，随后 PTP 打开并释放细胞色素 C，从而启动线粒体依赖性细胞凋亡[104]. Concurrently with Ca
与 Ca 同时²⁺ transport, there is a surge in ROS levels beyond the conventional threshold, leading to DNA damage and induction of apoptosis
运输，ROS 水平激增超过常规阈值，导致 DNA 损伤和诱导细胞凋亡[105]. Elevated Ca
.升高的 Ca²⁺ levels may be accompanied by the activation of calpain, which facilitates apoptosis or autophagy
水平可能伴随着钙蛋白酶的激活，从而促进细胞凋亡或自噬[106]. Furthermore, KEGG queries reveal the existence of crosstalk between
.此外，KEGG 查询揭示了Ca
钙²⁺ and various pathways, including Wnt/β-catenin and NF-κB signaling.
以及各种途径，包括 Wnt/β-catenin 和 NF-κB 信号传导。However, further experimental investigations are necessary to validate the anti-TNBC effect resulting from this interplay
然而，需要进一步的实验研究来验证这种相互作用产生的抗 TNBC 效应.

Naringin, quercetin, matrine and berberine, known as T2Rs agonists[107–109], have demonstrated anti-TNBC effects by targeting distinct pathways; however, the involvement of T2Rs in this process remains unclear. The T2Rs activator berberine exhibits anti-proliferative and pro-apoptotic effects in TNBC cells through the mitochondria-mediated apoptotic pathway[110]. However, further experiments are required to elucidate whether the phenomenon involves apoptosis triggered by nuclear or mitochondrial Ca²⁺ overload through T2Rs-mediated elevation of intracytoplasmic Ca²⁺ concentration.
柚皮苷、槲皮素、苦参碱和小檗碱被称为 T2Rs 激动剂[107–109]，通过靶向不同的途径证明了抗 TNBC 作用;然而，T2Rs 参与这一过程仍不清楚。T2Rs 激活剂小檗碱通过线粒体介导的凋亡途径在 TNBC 细胞中表现出抗增殖和促凋亡作用[110]。然而，需要进一步的实验来阐明该现象是否涉及 由 T2Rs 介导的胞浆内 Ca²⁺ 浓度升高的核或线粒体 Ca²⁺ 超负荷触发的细胞凋亡。

The activation of calpain by cisplatin and disulfiram has been demonstrated to induce apoptosis, as well as inhibit invasion and migration of TNBC cells[111,112]. RL71 disrupts intracytoplasmic Ca²⁺ homeostasis by inhibiting SERCA2 activity, leading to ERS, mitochondrial damage, and activation of the calmodulin-dependent protein kinase kinase (CaMKK)-Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR pathway, thereby inducing autophagy and apoptosis in TNBC cell lines[113]. This makes it possible to induce changes in intracellular Ca²⁺ homeostasis in the direction of T2Rs to generate anti-TNBC effects.
顺铂和双硫仑对钙蛋白酶的激活已被证明可诱导细胞凋亡，并抑制 TNBC 细胞的侵袭和迁移[111,112]。RL71 通过抑制 SERCA2 活性破坏胞浆内 Ca 2+ 稳态，导致 ERS、线粒体损伤和钙调蛋白依赖性蛋白激酶 （CaMKK）-腺苷 5'-单磷酸 （AMP） 活化蛋白激酶 （AMPK）-mTOR 通路的激活，从而诱导 TNBC 细胞系的自噬和细胞凋亡[113].这使得可以诱导细胞内 Ca^{2 +} 稳态沿 T2Rs 方向的变化以产生抗 TNBC 作用。

Conclusion and perspective
结论和观点

Tumorigenesis arises from mutations in a spectrum of cancer-specific hallmarks, encompassing self-sufficiency in growth signaling and evasion of apoptosis
肿瘤发生源于一系列癌症特异性标志物的突变，包括生长信号转导的自给自足和逃避细胞凋亡[114]. TNBC, characterized by its highly invasive nature, exhibits malignant features including rapid growth, high recurrence and metastasis rates, and a lack of targeted treatment options. Moreover, the currently employed chemotherapy and radiotherapy approaches are prone to drug resistance, resulting in a poorer prognosis. In comparison to other types of breast cancer with a five-year survival rate of 93%, TNBC has a significantly lower five-year survival rate of only 77%
.TNBC 的特点是其高度侵入性，表现出恶性特征，包括生长迅速、复发和转移率高以及缺乏靶向治疗方案。此外，目前采用的化疗和放疗方法容易产生耐药性，导致预后较差。与其他类型的乳腺癌（五年生存率为 93%）相比，TNBC 的五年生存率明显较低，仅为 77%[115]. The development of TNBC involves multiple signaling pathways, including PI3K/Akt/mTOR, NF-κB, Hedgehog. Targeting these mechanisms has long been recognized as a crucial approach to identify improved therapeutic strategies.
.TNBC 的发育涉及多种信号通路，包括 PI3K/Akt/mTOR、NF-κB、Hedgehog。长期以来，针对这些机制一直被认为是确定改进治疗策略的关键方法。To enhance the survival rate and treatment outcomes for TNBC patients, it is imperative to delve deeper into the molecular basis and intrinsic connections of these mechanisms while continuously exploring more effective therapeutic options that align with clinical needs
为了提高 TNBC 患者的生存率和治疗结果，必须更深入地研究这些机制的分子基础和内在联系，同时不断探索符合临床需求的更有效的治疗方案. Chinese herbal medicine, as a vital natural resource for the development of anticancer drugs
.中草药，作为抗癌药物开发的重要自然资源[11], has emerged as a prominent area of research.
已成为一个突出的研究领域。Adjuvant Chinese medicine exhibits potential in mitigating the adverse effects of chemotherapy and radiotherapy, enhancing the quality of life for patients with advanced breast cancer, and augmenting their survival rates
中药辅助治疗在减轻化疗和放疗的不良反应、提高晚期乳腺癌患者的生活质量和提高其生存率方面具有潜力[116]. We can summarize the effects of Chinese medicine against cancer into three points: I. Targeting different molecules to induce apoptosis, autophagy, and inhibit cell proliferation and metastasis; II. Regulating the immune microenvironment of tumors by enhancing autoimmune response function and inhibiting immune escape; III. Mitigating the side-effects of surgical and chemotherapeutic radiotherapy while improving patients' quality of survival. Nowadays, our focus has shifted from solely eradicating cancerous tissues to achieving a state of "coexistence with the tumor," promoting better harmony between our organism and cancerous tissues in order to prolong patient survival period and enhance their quality of life. Chinese medicine and herbs exhibit significant advantages in this regard
.我们可以将中医抗癌的效果归纳为三点：一、靶向不同分子诱导细胞凋亡、自噬，抑制细胞增殖和转移;II. 通过增强自身免疫反应功能，抑制免疫逃逸来调节肿瘤的免疫微环境;III. 减轻手术和化疗放疗的副作用，同时提高患者的生存质量。如今，我们的重点已经从单纯的根除癌组织转变为实现“与肿瘤共存”的状态，促进我们的机体与癌组织之间更好的和谐，以延长患者的生存期并提高他们的生活质量。中药和草药在这方面具有显着优势[117]. The therapeutic effects of Chinese herbs are attributed to their intricate bioactive ingredients, which confer the advantage of multi-targeting for treatment. For instance,
中草药的治疗效果归因于其复杂的生物活性成分，这赋予了多靶点治疗的优势。例如Bupleuri Radix collectively exhibits anticancer effects through a variety of compounds such as Saikosaponin D and quercetin
柴胡碱通过柴胡皂苷 D 和槲皮素等多种化合物共同发挥抗癌作用[118]. Alternatively, a single natural compound such as curcumin effectively impedes the progression of TNBC by selectively targeting diverse signaling pathways including PI3K/Akt, Wnt/β-catenin, Hedgehog, and
.或者，单一天然化合物（如姜黄素）通过选择性靶向多种信号通路（包括 PI3K/Akt、Wnt/β-catenin、Hedgehog 和other crucial cascades
其他关键级联[16,40,60]. In addition to the anticancer effects of bitter herbs discussed through identified bioactive ingredients, bitter compounds within these herbs may also regulate cellular physiopathological activities by stimulating T2Rs.
.除了通过鉴定的生物活性成分讨论苦味草药的抗癌作用外，这些草药中的苦味化合物还可以通过刺激 T2R 来调节细胞生理病理活动。However, further research is needed to fully understand this aspect of T2Rs and explore non-traditional pathways
然而，需要进一步的研究来充分了解 T2R 的这一方面并探索非传统途径. Therefore, future studies should consider various aspects. As previously mentioned, these bitter herbs and their natural constituents exert effects on multiple signaling pathways; however, the intrinsic relevance remains unclear, and current research on Chinese herbal medicines primarily consists of laboratory studies with a limited number of randomized clinical trials
.因此，未来的研究应考虑各个方面。如前所述，这些苦味草本及其天然成分对多种信号通路产生影响;然而，其内在相关性仍不清楚，目前对中草药的研究主要包括实验室研究和有限数量的随机临床试验[119]. Furthermore, there is still a need for comprehensive investigation into the biometabolic activity of compound
.此外，仍需要对化合物的生物代谢活性进行全面研究[120]. Some of the bitter herbs exhibit toxic effects, necessitating an evaluation of their safety. Extracts or isolated active ingredients do not accurately represent the entirety of the herbal medicine, and most laboratory studies tend to focus on a single component while disregarding its overall impact. When employing Chinese medicine formulations containing herbal medicines, it is crucial to consider the corresponding ingredient content and bioavailability, as well as prepare patients for long-term drug usage. In future molecular targeted therapy for cancer, it is imperative to conduct further research involving rigorously designed potential herbal trials.
.一些苦草表现出毒性作用，需要评估其安全性。提取物或分离的活性成分并不能准确代表草药的全部，大多数实验室研究往往只关注单一成分，而忽视其整体影响。当使用含有草药的中药制剂时，考虑相应的成分含量和生物利用度以及为患者长期使用药物做好准备至关重要。在未来的癌症分子靶向治疗中，必须进行进一步的研究，包括严格设计的潜在草药试验。

In conclusion, bitter herbs and their bioactive constituents exhibit promising potential in the treatment of TNBC, with additional targets yet to be explored. These findings hold significant implications for inhibiting TNBC onset and progression, as well as reducing the risk of recurrence and metastasis.
总之，苦味草药及其生物活性成分在治疗 TNBC 方面显示出有希望的潜力，但其他靶点还有待探索。这些发现对于抑制 TNBC 的发生和进展以及降低复发和转移的风险具有重要意义。

ACKNOWLEDGMENTS
确认

The authers greatly appreciate Dr. ML, a doctor of clinical medicine from Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine. This work was supported by National Natural Science Foundation of China (number: 82274423).
评审员非常感谢南京中医药大学附属苏州中医院临床医学博士 ML 博士。这项工作得到了中国国家自然科学基金（编号：82274423）的支持。

Author contributions
作者贡献

ZAW contributed to the conceptualisation, data curation, formal analysis, investigation, resources, visualization, and writing (original draft). ML contributed to the supervision, conceptualisation, resources, and writing (review and editing). MHZ, SJL contributed to the investigation, resources, and data curation. All authors contributed to the article and approved the submitted version article and approved the submitted version.
ZAW 为概念化、数据管理、形式分析、调查、资源、可视化和写作（原始草案）做出了贡献。ML 为监督、概念化、资源和写作（审查和编辑）做出了贡献。MHZ、SJL 为调查、资源和数据管理做出了贡献。所有作者都为文章做出了贡献，并批准了提交的版本文章，并批准了提交的版本。

CoNFLict of interest
感兴趣的 CoNFLict

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
作者声明，该研究是在没有任何可能被解释为潜在利益冲突的商业或财务关系的情况下进行的。

References:
参考资料：

1.  H, S.; J, F.; Rl, S.; M, L.; I, S.; A, J.; F, B. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin. 2021, 71, doi:10.3322/caac.21660.
1. H， S.;J， F.;Rl， S.;M， L.;I， S.;A， J.;F， B. 2020 年全球癌症统计：GLOBOCAN 对全球 185 个国家 36 种癌症的发病率和死亡率的估计。癌症 J. 克林。2021， 71， doi：10.3322/caac.21660.

2.  S, L.; R, Z.; S, Z.; R, C.; S, W.; K, S.; H, Z.; W, W.; J, H. Breast Cancer Incidence and Mortality in Women in China: Temporal Trends and Projections to 2030. Cancer Biol. Med. 2021, 18, doi:10.20892/j.issn.2095-3941.2020.0523.
2. S， L.;R， Z.;S， Z.;R， C.;S， W.;K， S.;H， Z.;W， W.;J， H. 中国女性乳腺癌发病率和死亡率：到 2030 年的时间趋势和预测。癌症生物学医学2021， 18， doi：10.20892/j.issn.2095-3941.2020.0523.

3.  Tc, P.; Ma, A.; J, M.; S, G.; N, G.; M, N.; Ag, L.; Ih, S.; Lt, D. Delays in Breast Cancer Care by Race and Sexual Orientation: Results from a National Survey with Diverse Women in the United States. Cancer 2021, 127, doi:10.1002/cncr.33629.
3. Tc， P.;马，A.;J， M.;S， G.;N， G.;M， N.;Ag， L.;Ih， S.;Lt， D. 按种族和性取向划分的乳腺癌护理延迟：美国不同女性全国调查结果。癌症2021， 127， doi：10.1002/cncr.33629.

4.  C, D.; C, L.; A, T.; G, von M. Molecular Alterations in Triple-Negative Breast Cancer-the Road to New Treatment Strategies. Lancet Lond. Engl. 2017, 389, doi:10.1016/S0140-6736(16)32454-0.
4. C， D.;C， L.;A， T.;G， von M. 三阴性乳腺癌的分子改变 - 新治疗策略之路。柳叶刀 Lond. Engl.2017， 389， doi：10.1016/S0140-6736（16）32454-0.

5.  R, D.; M, T.; Ki, P.; Wm, H.; Hk, K.; Ca, S.; La, L.; E, R.; P, S.; Sa, N. Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2007, 13, doi:10.1158/1078-0432.CCR-06-3045.
5. R， D.;M， T.;基，P.;Wm， H.;香港，K.;卡，S.;洛杉矶;E， R.;P， S.;Sa， N. 三阴性乳腺癌：临床特征和复发模式。克林。癌症研究 Off. J. Am. Assoc. Cancer Res.2007， 13， doi：10.1158/1078-0432.CCR-06-3045.

6.  Lu, X.; Kang, Y. Organotropism of Breast Cancer Metastasis. J. Mammary Gland Biol. Neoplasia 2007, 12, 153–162, doi:10.1007/s10911-007-9047-3.
6. 卢 X.;Kang， Y. 乳腺癌转移的器官趋向性。肿瘤形成2007， 12， 153–162， doi：10.1007/s10911-007-9047-3。

7.  L, J.; B, H.; E, S.; Y, C.; A, G.; X, C. Breast Cancer Lung Metastasis: Molecular Biology and Therapeutic Implications. Cancer Biol. Ther. 2018, 19, doi:10.1080/15384047.2018.1456599.
7. L， J.;B， H.;E， S.;Y， C.;A， G.;X， C. 乳腺癌肺转移：分子生物学和治疗意义。癌症生物学。2018， 19， doi：10.1080/15384047.2018.1456599.

8.  Bd, L.; B, J.; X, C.; Mv, E.; Kn, J.; Y, S.; Hl, M.; Me, S.; Ja, P. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PloS One 2016, 11, doi:10.1371/journal.pone.0157368.
8. Bd， L.;B， J.;X， C.;Mv， E.;Kn， J.;Y， S.;赫尔，M.;我，S.;Ja， P. 三阴性乳腺癌分子亚型的改进：对新辅助化疗选择的影响。公共科学图书馆一号2016， 11， doi：10.1371/journal.pone.0157368.

9.  Vs, J.; N, S.; Na, M.; P, K.; M, L.; N, S. Therapeutic Targets of Triple-Negative Breast Cancer: A Review. Br. J. Pharmacol. 2015, 172, doi:10.1111/bph.13211.
9. Vs， J.;N， S.;娜，M.;P， K.;M， L.;N， S. 三阴性乳腺癌的治疗靶点：综述。Br. J. 药理学。2015， 172， doi：10.1111/bph.13211.

10.  S, Z.; Y, W.; B, S.; M, Y.; Y, Y.; Q, M.; K, W. Recent Advances in Targeted Strategies for Triple-Negative Breast Cancer. J. Hematol. Oncol.J Hematol Oncol 2023, 16, doi:10.1186/s13045-023-01497-3.
10. S， Z.;Y， W.;B， S.;M， Y.;Y， Y.;Q， M.;K，W.三阴性乳腺癌靶向策略的最新进展。J. 血醇。Oncol.J 血醇 Oncol2023， 16， doi：10.1186/s13045-023-01497-3。

11.  D, B.; C, G.; F, D.A.; M, L.; S, A. Natural Products as Promising Antitumoral Agents in Breast Cancer: Mechanisms of Action and Molecular Targets. Mini Rev. Med. Chem. 2016, 16, doi:10.2174/1389557515666150709110959.
11. D， B.;C， G.;F， D.A.;M， L.;S， A. 天然产物作为乳腺癌中很有前途的抗肿瘤药物：作用机制和分子靶标。Mini Rev. Med. Chem.2016， 16， doi：10.2174/1389557515666150709110959.

12.  Buyel, J.F. Plants as Sources of Natural and Recombinant Anti-Cancer Agents. Biotechnol. Adv. 2018, 36, 506–520, doi:10.1016/j.biotechadv.2018.02.002.
12. Buyel， J.F. 植物作为天然和重组抗癌剂的来源。 生物技术 Adv.2018， 36， 506–520， doi：10.1016/j.biotechadv.2018.02.002.

13.  J, C.; Kl, M.; Ma, H.; E, A.; L, F.; W, G.; Cs, Z.; Nj, R. T2Rs Function as Bitter Taste Receptors. Cell 2000, 100, doi:10.1016/s0092-8674(00)80706-0.
13. J， C.;Kl， M.;马，H.;E， A.;L， F.;W， G.;Cs， Z.;Nj， R. T2Rs 起苦味受体的作用。细胞2000， 100， doi：10.1016/s0092-8674（00）80706-0.

14.  Avau, B.; Depoortere, I. The Bitter Truth about Bitter Taste Receptors: Beyond Sensing Bitter in the Oral Cavity. Acta Physiol. Oxf. Engl. 2016, 216, 407–420, doi:10.1111/apha.12621.
14. 阿沃，B.;德普尔特尔，I.关于苦味受体的苦涩真相：超越在口腔中感知苦涩。物理学杂志 Oxf. Engl.2016， 216， 407–420， doi：10.1111/apha.12621.

15.  Xx, D.; Yn, J.; Hf, H.; D, X.; Cc, B.; Sy, H. Taraxacum Mongolicum Extract Inhibited Malignant Phenotype of Triple-Negative Breast Cancer Cells in Tumor-Associated Macrophages Microenvironment through Suppressing IL-10 / STAT3 / PD-L1 Signaling Pathways. J. Ethnopharmacol. 2021, 274, doi:10.1016/j.jep.2021.113978.
15. xx， d.;Yn， J.;Hf， H.;D， X.;Cc, B.;Sy， H. taraxacum mongolicum 提取物通过抑制 IL-10 / STAT3 / PD-L1 信号通路抑制肿瘤相关巨噬细胞微环境中三阴性乳腺癌细胞的恶性表型。J. 民族药理学。2021， 274， doi：10.1016/j.jep.2021.113978.

16.  G, M.-G.; Ea, M.-P.; J, G.-Q.; E, A.; R, G.-B.; A, Z.-D.; F, L.; L, D. Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin. Int. J. Mol. Sci. 2022, 23, doi:10.3390/ijms23147659.
16. G，M.-G.;Ea，MP;J， G.-Q.;E， A.;R， G.-B.;A， Z.-D.;F， L.;L， D. 骨化三醇和姜黄素抑制人三阴性乳腺癌细胞中血管生成模拟的内皮依赖性诱导。国际分子科学杂志2022， 23， doi：10.3390/ijms23147659.

17.  W, X.; Y, Z.; S, Z.; F, W.; K, Z.; Y, H.; Z, Z.; G, H.; J, W. Oxymatrine Enhanced Anti-Tumor Effects of Bevacizumab against Triple-Negative Breast Cancer via Abating Wnt/β-Catenin Signaling Pathway. Am. J. Cancer Res. 2019, 9.
17. W， X.;Y， Z.;S， Z.;F， W.;K， Z.;Y， H.;Z， Z.;G， H.;J， W. 氧化苦参碱通过减少 Wnt/β-连环蛋白信号通路增强贝伐珠单抗对三阴性乳腺癌的抗肿瘤作用。美国癌症研究杂志2019 年，9 页。

18.  J, D. mTOR Signaling and Drug Development in Cancer. Nat. Rev. Clin. Oncol. 2010, 7, doi:10.1038/nrclinonc.2010.21.
18. J， D. 癌症中的 mTOR 信号传导和药物开发。 Nat. Rev. Clin.Oncol.2010， 7， doi：10.1038/nrclinonc.2010.21.

19.  S, W.; L, F.; C, Q.; D, E.; Ew, M.; A, P.; Mj, D. mTOR in Breast Cancer: Differential Expression in Triple-Negative and Non-Triple-Negative Tumors. Breast Edinb. Scotl. 2012, 21, doi:10.1016/j.breast.2011.09.008.
19. S， W.;L， F.;C， Q.;D， E.;呃，M.;A， P.;Mj， D. mTOR 在乳腺癌中：三阴性和非三阴性肿瘤中的差异表达。乳房 Edinb.苏格兰。2012， 21， doi：10.1016/j.breast.2011.09.008.

20.  Kim, J.; Kundu, M.; Viollet, B.; Guan, K.-L. AMPK and mTOR Regulate Autophagy through Direct Phosphorylation of Ulk1. Nat. Cell Biol. 2011, 13, 132–141, doi:10.1038/ncb2152.
20. 金 J.;昆杜，M.;维奥莱特，B.;关 K.-L.AMPK 和 mTOR 通过直接磷酸化 Ulk1 调节自噬。Nat. 细胞生物学2011， 13， 132–141， doi：10.1038/ncb2152.

21.  C, L.; Y, W.; C, W.; Y, C.; Z, J. The Anti-Migration and Anti-Invasion Effects of Bruceine D in Human Triple-Negative Breast Cancer MDA-MB-231 Cells. Exp. Ther. Med. 2020, 19, doi:10.3892/etm.2019.8187.
21. C， L.;Y， W.;C， W.;Y， C.;Z， J.Bruceine D 在人三阴性乳腺癌 MDA-MB-231 细胞中的抗迁移和抗侵袭作用。Exp. Ther. Med.2020， 19， doi：10.3892/etm.2019.8187.

22.  Wei, S.; Zhang, Y.; Ma, X.; Yao, Y.; Zhou, Q.; Zhang, W.; Zhou, C.; Zhuang, J. MAT as a Promising Therapeutic Strategy against Triple-Negative Breast Cancer via Inhibiting PI3K/AKT Pathway. Sci. Rep. 2023, 13, 12351, doi:10.1038/s41598-023-39655-9.
22. 魏 S.;张 Y.;马，X.;姚 Y.;周，Q.;张 W.;周， C.;Zhuang， J. MAT 作为一种很有前途的通过抑制 PI3K/AKT 通路对抗三阴性乳腺癌的治疗策略。科学代表2023， 13， 12351， doi：10.1038/s41598-023-39655-9.

23.  W, C.; D, L.; M, G.; H, L.; Q, W. Rubioncolin C, a Natural Naphthohydroquinone Dimer Isolated from Rubia Yunnanensis, Inhibits the Proliferation and Metastasis by Inducing ROS-Mediated Apoptotic and Autophagic Cell Death in Triple-Negative Breast Cancer Cells. Drug Dev. Res. 2022, 83, doi:10.1002/ddr.21938.
23. W， C.;D， L.;M， G.;H， L.;Q， W. Rubioncolin C 是从 Rubia Yunnanensis 中分离的天然萘氢醌二聚体，通过诱导 ROS 介导的三阴性乳腺癌细胞凋亡和自噬细胞死亡来抑制增殖和转移。药物开发研究2022， 83， doi：10.1002/ddr.21938.

24.  L, L.; J, W.; L, F.; J, F.; J, W.; N, T.; Z, W. Rubioncolin C, a Natural Naphthohydroquinone Dimer Isolated from Rubia Yunnanensis, Inhibits the Proliferation and Metastasis by Inducing ROS-Mediated Apoptotic and Autophagic Cell Death in Triple-Negative Breast Cancer Cells. J. Ethnopharmacol. 2021, 277, doi:10.1016/j.jep.2021.114184.
24. L，L.;J， W.;L， F.;J， F.;J， W.;N， T.;Z， W. Rubioncolin C 是一种从云南红叶中分离的天然萘氢醌二聚体，通过诱导 ROS 介导的三阴性乳腺癌细胞凋亡和自噬细胞死亡来抑制增殖和转移。J. 民族药理学。2021， 277， doi：10.1016/j.jep.2021.114184.

25.  Tian, D.; Yang, Y.; Yu, M.; Han, Z.-Z.; Wei, M.; Zhang, H.-W.; Jia, H.-M.; Zou, Z.-M. Anti-Inflammatory Chemical Constituents of Flos Chrysanthemi Indici Determined by UPLC-MS/MS Integrated with Network Pharmacology. Food Funct. 2020, 11, 6340–6351, doi:10.1039/d0fo01000f.
25. 田 D.;杨 Y.;余，M.;韩，Z.-Z.;魏，M.;张 H.-W.;贾，HM;邹 Z.-M.通过 UPLC-MS/MS 结合网络药理学测定菊花的抗炎化学成分。食品功能。2020， 11， 6340–6351， doi：10.1039/d0fo01000f.

26.  Y, L.; Y, C.; D, S.-W. The Potential of Dandelion in the Fight against Gastrointestinal Diseases: A Review. J. Ethnopharmacol. 2022, 293, doi:10.1016/j.jep.2022.115272.
26. Y， L.;Y， C.;D， S.-W.蒲公英在对抗胃肠道疾病中的潜力：综述。J. 民族药理学。2022， 293， doi：10.1016/j.jep.2022.115272.

27.  Ht, W.; J, L.; Ye, L.; Hf, C.; Kw, H.; Sh, L.; Ky, P.; Kj, L.; Cc, H.; Dr, C. Luteolin Suppresses Androgen Receptor-Positive Triple-Negative Breast Cancer Cell Proliferation and Metastasis by Epigenetic Regulation of MMP9 Expression via the AKT/mTOR Signaling Pathway. Phytomedicine Int. J. Phytother. Phytopharm. 2021, 81, doi:10.1016/j.phymed.2020.153437.
27. Ht， W.;J， L.;叶，L.;Hf， C.;Kw， H.;Sh， L.;Ky， P.;KJ，L.;Cc, H.;C. 木犀草素博士通过 AKT/mTOR 信号通路对 MMP9 表达的表观遗传调控抑制雄激素受体阳性三阴性乳腺癌细胞增殖和转移。植物医学 Int. J. Phytother.植物药剂。2021， 81， doi：10.1016/j.phymed.2020.153437.

28.  T, E.; F, O. Anti-Inflammatory and Anti-Cancer Activities of Frankincense: Targets, Treatments and Toxicities. Semin. Cancer Biol. 2022, 80, doi:10.1016/j.semcancer.2020.01.015.
28. T， E.;F， O. 乳香的抗炎和抗癌活性：靶点、治疗和毒性。精明。癌症生物学。2022， 80， doi：10.1016/j.semcancer.2020.01.015.

29.  X, Z.; Z, G.; K, C.; Q, Z.; M, C.; J, W.; X, L.; L, W. Lupeol Inhibits the Proliferation and Migration of MDA-MB-231 Breast Cancer Cells via a Novel Crosstalk Mechanism between Autophagy and the EMT. Food Funct. 2022, 13, doi:10.1039/d2fo00483f.
29. X， Z.;Z， G.;K， C.;Q， Z.;M， C.;J， W.;X， L.;L， W. Lupeol 通过自噬和 EMT 之间的新型串扰机制抑制 MDA-MB-231 乳腺癌细胞的增殖和迁移。食品功能。2022， 13， doi：10.1039/d2fo00483f.

30.  Z, X.; X, H.; D, O.; T, L.; Z, L.; G, J.; J, L.; J, Z. Targeting PI3K/AKT/mTOR-Mediated Autophagy for Tumor Therapy. Appl. Microbiol. Biotechnol. 2020, 104, doi:10.1007/s00253-019-10257-8.
30. Z， X.;X， H.;D， O.;T， L.;Z，L.;G， J.;J， L.;靶向 PI3K/AKT/mTOR 介导的自噬用于肿瘤治疗。应用微生物学。生物技术。2020， 104， doi：10.1007/s00253-019-10257-8.

31.  S, Z.; T, C.; Y, D.; H, Z.; B, W.; H, C.; J, N.; Y, S.; None, X.-A.L. Radix Tetrastigma Extracts Enhance the Chemosensitivity in Triple-Negative Breast Cancer Via Inhibiting PI3K/Akt/mTOR-Mediated Autophagy. Clin. Breast Cancer 2022, 22, doi:10.1016/j.clbc.2021.07.015.
31. S， Z.;T， C.;Y， D.;H， Z.;B， W.;H， C.;J， N.;Y， S.;无，X.-A.L.Radix tetrastigma 提取物通过抑制 PI3K/Akt/mTOR 介导的自噬增强三阴性乳腺癌的化学敏感性。克林。乳腺癌2022， 22， doi：10.1016/j.clbc.2021.07.015.

32.  Bt, M.; K, T.; X, H. Wnt/Beta-Catenin Signaling: Components, Mechanisms, and Diseases. Dev. Cell 2009, 17, doi:10.1016/j.devcel.2009.06.016.
32. Bt，M.;K，T.;X， H. Wnt/β-连环蛋白信号传导：成分、机制和疾病。开发细胞2009， 17， doi：10.1016/j.devcel.2009.06.016.

33.  Geyer, F.C.; Lacroix-Triki, M.; Savage, K.; Arnedos, M.; Lambros, M.B.; MacKay, A.; Natrajan, R.; Reis-Filho, J.S. β-Catenin Pathway Activation in Breast Cancer Is Associated with Triple-Negative Phenotype but Not with CTNNB1 Mutation. Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc 2011, 24, 209–231, doi:10.1038/modpathol.2010.205.
33. 盖尔，FC;拉克鲁瓦-特里基，M.;萨维奇，K.;阿内多斯，M.;兰布罗斯，MB;麦凯，A.;纳特拉詹，R.;Reis-Filho， JS 乳腺癌中的 β-连环蛋白通路激活与三阴性表型相关，但与 CTNNB1 突变无关。国防部。病理学。Off. J. U. S. Can. Acad. Pathol.公司2011， 24， 209–231， doi：10.1038/modpathol.2010.205.

34.  J, W.; H, Q.; X, Z.; W, S.; F, X.; T, H.; H, Z.; A, W.; G, L.; Y, L.; et al. Saikosaponin D from Radix Bupleuri Suppresses Triple-Negative Breast Cancer Cell Growth by Targeting β-Catenin Signaling. Biomed. Pharmacother. Biomedecine Pharmacother. 2018, 108, doi:10.1016/j.biopha.2018.09.038.
34. J， W.;H， Q.;X， Z.;W， S.;F， X.;T， H.;H， Z.;A， W.;G， L.;Y， L.;等人来自柴胡的柴胡皂苷 D 通过靶向 β-连环蛋白信号传导抑制三阴性乳腺癌细胞生长。生物医学。药剂师。生物美地碱药剂。2018， 108， doi：10.1016/j.biopha.2018.09.038.

35.  Mei, X.; Gohal, S.A.; Alatwi, E.S.; Hui, Y.; Yang, C.; Song, Y.; Zhou, C.; Liu, M.-C. Sulfation of Quercitrin, Epicatechin and Rutin by Human Cytosolic Sulfotransferases (SULTs): Differential Effects of SULT Genetic Polymorphisms. Planta Med. 2021, 87, 498–506, doi:10.1055/a-1351-0618.
35. 梅，X.;戈哈尔，SA;阿拉特维，ES;许 Y.;杨 C.;宋 Y.;周， C.;刘 M.-C.人胞质磺基转移酶 （SULT） 对槲皮素、表儿茶素和芦丁的硫酸化：SULT 遗传多态性的不同效应。植物医学。2021， 87， 498–506， doi：10.1055/a-1351-0618.

36.  A, S.; C, T.; Y, L.; S, S.; Rb, D.; P, S.; A, L. Quercetin Regulates β-Catenin Signaling and Reduces the Migration of Triple Negative Breast Cancer. Mol. Carcinog. 2016, 55, doi:10.1002/mc.22318.
36. A， S.;C， T.;Y， L.;S， S.;Rb， D.;P， S.;A， L. Quercetin 调节 β-catenin 信号传导并减少三阴性乳腺癌的迁移。Mol. Carcinog.2016， 55， doi：10.1002/mc.22318.

37.  Wang, W.; Jiang, S.; Zhao, Y.; Zhu, G. Echinacoside: A Promising Active Natural Products and Pharmacological Agents. Pharmacol. Res. 2023, 197, 106951, doi:10.1016/j.phrs.2023.106951.
37. 王 W.;江 S.;赵 Y.;Zhu， G. 松果菊苷：一种有前途的活性天然产物和药理制剂。药理学研究2023， 197， 106951， doi：10.1016/j.phrs.2023.106951.

38.  C, T.; L, G.; None, L.X.; K, Q.; Z, Z.; L, W. Echinacoside Inhibits Breast Cancer Cells by Suppressing the Wnt/β-Catenin Signaling Pathway. Biochem. Biophys. Res. Commun. 2020, 526, doi:10.1016/j.bbrc.2020.03.050.
38. C， T.;L， G.;无，L.X.;K， Q.;Z， Z.;L， W. Echinacoside 通过抑制 Wnt/β-catenin 信号通路抑制乳腺癌细胞。生化。生物物理学。Res. Commun.2020， 526， doi：10.1016/j.bbrc.2020.03.050.

39.  W, L.; C, L.; Td, K.; H, C.; Rc, R.; Y, L. Silibinin Inhibits Wnt/β-Catenin Signaling by Suppressing Wnt Co-Receptor LRP6 Expression in Human Prostate and Breast Cancer Cells. Cell. Signal. 2012, 24, doi:10.1016/j.cellsig.2012.07.009.
39. W， L.;C， L.;TD，K.;H， C.;Rc， R.;Y， L. silibinin 通过抑制人前列腺癌细胞和 Breast 癌细胞中 Wnt 辅受体 LRP6 的表达来抑制 Wnt/β-catenin 信号传导。细胞。信号。2012， 24， doi：10.1016/j.cellsig.2012.07.009.

40.  Cp, P.; G, R.; S, M.; D, B.; R, R. Potent Growth Suppressive Activity of Curcumin in Human Breast Cancer Cells: Modulation of Wnt/Beta-Catenin Signaling. Chem. Biol. Interact. 2009, 181, doi:10.1016/j.cbi.2009.06.012.
40. CP，P.;G， R.;S，M.;D， B.;R， R. 姜黄素在人乳腺癌细胞中的有效生长抑制活性：Wnt/β-连环蛋白信号传导的调节。化学生物学相互作用。2009， 181， doi：10.1016/j.cbi.2009.06.012.

41.  D, G.; J, W.; X, W.; H, L.; H, Z.; D, C.; L, C.; N, H. Double Directional Adjusting Estrogenic Effect of Naringin from Rhizoma Drynariae (Gusuibu). J. Ethnopharmacol. 2011, 138, doi:10.1016/j.jep.2011.09.034.
41. D， G.;J， W.;X， W.;H， L.;H， Z.;D， C.;L， C.;N，H. 来自 Rhizoma Drynariae （Gusuibu） 的柚皮苷的双向调节雌激素作用。J. 民族药理学。2011， 138， doi：10.1016/j.jep.2011.09.034.

42.  Bai, Y.; Zheng, Y.; Pang, W.; Peng, W.; Wu, H.; Yao, H.; Li, P.; Deng, W.; Cheng, J.; Su, W. Identification and Comparison of Constituents of Aurantii Fructus and Aurantii Fructus Immaturus by UFLC-DAD-Triple TOF-MS/MS. Mol. Basel Switz. 2018, 23, 803, doi:10.3390/molecules23040803.
42. 白 Y.;郑 Y.;庞，W.;彭，W.;吴 H.;姚 H.;李 P.;邓，W.;程 J.;Su， W. 通过 UFLC-DAD-Triple TOF-MS/MS 鉴定和比较 Aurantii fructus 和 Aurantii fructus immaturus 的成分。 巴塞尔斯威茨分子。2018， 23， 803， doi：10.3390/molecules23040803.

43.  Tistaert, C.; Thierry, L.; Szandrach, A.; Dejaegher, B.; Fan, G.; Frédérich, M.; Vander Heyden, Y. Quality Control of Citri Reticulatae Pericarpium: Exploratory Analysis and Discrimination. Anal. Chim. Acta 2011, 705, 111–122, doi:10.1016/j.aca.2011.04.024.
43. 蒂斯塔特，C.;蒂埃里，L.;赞德拉赫，A.;Dejaegher， B.;范 G.;弗雷德里希，M.;Vander Heyden， Y. Citri reticulatae 果皮的质量控制：探索性分析和鉴别。肛门。实用报章2011， 705， 111–122， doi：10.1016/j.aca.2011.04.024.

44.  H, L.; B, Y.; J, H.; T, X.; X, Y.; J, W.; F, L.; L, Z.; H, L.; G, R. Naringin Inhibits Growth Potential of Human Triple-Negative Breast Cancer Cells by Targeting β-Catenin Signaling Pathway. Toxicol. Lett. 2013, 220, doi:10.1016/j.toxlet.2013.05.006.
44. H， L.;B， Y.;J， H.;T， X.;X， Y.;J， W.;F， L.;L， Z.;H， L.;G， R. Naringin 通过靶向 β-catenin 信号通路抑制人三阴性乳腺癌细胞的生长潜力。毒理学。莱特。2013， 220， doi：10.1016/j.toxlet.2013.05.006.

45.  H, S.; J, M.; T, G.; R, H. Triptolide Induces Apoptosis of Breast Cancer Cells via a Mechanism Associated with the Wnt/β-Catenin Signaling Pathway. Exp. Ther. Med. 2014, 8, doi:10.3892/etm.2014.1729.
45. H， S.;J， M.;T， G.;R， H. 雷公藤内酯通过与 Wnt/β-连环蛋白信号通路相关的机制诱导乳腺癌细胞凋亡。Exp. Ther. Med.2014， 8， doi：10.3892/etm.2014.1729.

46.  Xia, Y.; Shen, S.; Verma, I.M. NF-κB, an Active Player in Human Cancers. Cancer Immunol. Res. 2014, 2, 823–830, doi:10.1158/2326-6066.CIR-14-0112.
46. 夏 Y.;沈 S.;Verma，IM NF-κB，人类癌症的活跃参与者。癌症免疫学研究2014， 2， 823–830， doi：10.1158/2326-6066.CIR-14-0112.

47.  Yamaguchi, N.; Ito, T.; Azuma, S.; Ito, E.; Honma, R.; Yanagisawa, Y.; Nishikawa, A.; Kawamura, M.; Imai, J.; Watanabe, S.; et al. Constitutive Activation of Nuclear Factor-kappaB Is Preferentially Involved in the Proliferation of Basal-like Subtype Breast Cancer Cell Lines. Cancer Sci. 2009, 100, 1668–1674, doi:10.1111/j.1349-7006.2009.01228.x.
47. 山口，N.;伊藤，T.;Azuma， S.;伊藤，E.;本间，R.;柳泽，Y.;西川，A.;川村，M.;今井，J.;渡边，S.;等人。核因子-kappaB 的组成型激活优先参与基底样亚型乳腺癌细胞系的增殖。癌症科学2009， 100， 1668–1674， doi：10.1111/j.1349-7006.2009.01228.x.

48.  Sk, M.; By, C.; Ch, K. ERK1/2 Mediates TNF-Alpha-Induced Matrix Metalloproteinase-9 Expression in Human Vascular Smooth Muscle Cells via the Regulation of NF-kappaB and AP-1: Involvement of the Ras Dependent Pathway. J. Cell. Physiol. 2004, 198, doi:10.1002/jcp.10435.
48. Sk， M.;作者 C.;Ch， K. ERK1/2 通过调节 NF-kappaB 和 AP-1 介导 TNF-α 诱导的人血管平滑肌细胞基质金属蛋白酶-9 表达：参与 Ras 依赖性途径。J. 细胞。生理学。2004， 198， doi：10.1002/jcp.10435.

49.  Shrivastava, S.; Kulkarni, P.; Thummuri, D.; Jeengar, M.K.; Naidu, V.G.M.; Alvala, M.; Redddy, G.B.; Ramakrishna, S. Piperlongumine, an Alkaloid Causes Inhibition of PI3 K/Akt/mTOR Signaling Axis to Induce Caspase-Dependent Apoptosis in Human Triple-Negative Breast Cancer Cells. Apoptosis Int. J. Program. Cell Death 2014, 19, 1148–1164, doi:10.1007/s10495-014-0991-2.
49. Shrivastava， S.;库尔卡尼，P.;图穆里，D.;詹加尔，MK;奈杜，V.G.M.;阿尔瓦拉，M.;雷迪，GB;Ramakrishna， S. Piperlongumine，一种生物碱，抑制 PI3 K/AKT/mTOR 信号轴，诱导人三阴性乳腺癌细胞中 Caspase 依赖性细胞凋亡。细胞凋亡国际杂志计划。细胞死亡2014， 19， 1148–1164， doi：10.1007/s10495-014-0991-2。

50.  Li, X.; Yan, H.; Pang, X.; Sha, N.; Hua, H.; Wu, L.; Guo, D. Chemical constituents of flavonoids from rhizome of Sophora tonkinensis. Zhongguo Zhong Yao Za Zhi Zhongguo Zhongyao Zazhi China J. Chin. Mater. Medica 2009, 34, 282–285.
50. 李 X.;严，H.;庞 X.;沙，N.;华， H.;吴 L.;Guo， D. 苦参根茎中黄酮类化合物的化学成分。Zhongguo Zhong Yao Za Zhi Zhongguo Zhongyao Zazhi China J. Chin.母公司。医学2009， 34， 282–285。

51.  H, P.; W, Z.; W, H.; X, L.; Q, D.; L, L.; X, Z.; S, W. Genistein Inhibits MDA-MB-231 Triple-Negative Breast Cancer Cell Growth by Inhibiting NF-κB Activity via the Notch-1 Pathway. Int. J. Mol. Med. 2012, 30, doi:10.3892/ijmm.2012.990.
51. H， P.;W， Z.;W， H.;X， L.;Q， D.;L， L.;X， Z.;S， W. Genistein 通过 Notch-1 通路抑制 NF-κB 活性，从而抑制 MDA-MB-231 三阴性乳腺癌细胞生长。国际 J. Mol. Med.2012， 30， doi：10.3892/ijmm.2012.990.

52.  Z, L.; J, L.; B, M.; C, H.; H, L.; H, Q.; X, W.; J, X. Genistein Induces Cell Apoptosis in MDA-MB-231 Breast Cancer Cells via the Mitogen-Activated Protein Kinase Pathway. Toxicol. Vitro Int. J. Publ. Assoc. BIBRA 2008, 22, doi:10.1016/j.tiv.2008.08.001.
52. Z， L.;J， L.;B，M.;C， H.;H， L.;H， Q.;X， W.;J， X. Genistein 通过丝裂原活化蛋白激酶途径诱导 MDA-MB-231 乳腺癌细胞凋亡。毒理学。Vitro Int. J. Publ. Assoc. BIBRA2008， 22， doi：10.1016/j.tiv.2008.08.001.

53.  H, T.; M, Z.; L, X.; X, Z.; Y, Z. Gypensapogenin H Suppresses Tumor Growth and Cell Migration in Triple-Negative Breast Cancer by Regulating PI3K/AKT/NF-κB/MMP-9 Signaling Pathway. Bioorganic Chem. 2022, 126, doi:10.1016/j.bioorg.2022.105913.
53. H， T.;M， Z.;L， X.;X， Z.;Y， Z. gypensapogenin H 通过调节 PI3K/AKT/NF-κB/MMP-9 信号通路抑制三阴性乳腺癌的肿瘤生长和细胞迁移。生物有机化学2022， 126， doi：10.1016/j.bioorg.2022.105913.

54.  E, K.; Yj, K.; Z, J.; Jm, K.; M, W.; Kr, P.; Ja, S.; K, O.; Ja, K.; K, E.-M.; et al. ROR Activation by Nobiletin Enhances Antitumor Efficacy via Suppression of IκB/NF-κB Signaling in Triple-Negative Breast Cancer. Cell Death Dis. 2022, 13, doi:10.1038/s41419-022-04826-5.
54. E， K.;Yj， K.;Z， J.;Jm， K.;M， W.;克尔，P.;贾，S.;K， O.;贾，K.;K，E.-M.;等人. 川陈皮素的 ROR 激活通过抑制三阴性乳腺癌中的 IκB/NF-κB 信号传导增强抗肿瘤疗效。细胞死亡 Dis.2022， 13， doi：10.1038/s41419-022-04826-5.

55.  Pl, K.; Yl, H.; Tc, L.; Ws, T.; Yy, C.; Cc, L. Rugosin E, an Ellagitannin, Inhibits MDA-MB-231 Human Breast Cancer Cell Proliferation and Induces Apoptosis by Inhibiting Nuclear Factor-kappaB Signaling Pathway. Cancer Lett. 2007, 248, doi:10.1016/j.canlet.2006.08.006.
55. Pl， K.;伊尔，H.;Tc， L.;Ws， T.;Yy， C.;Cc， L. rugosin E，一种鞣花单宁，通过抑制核因子-κB 信号通路抑制 MDA-MB-231 人乳腺癌细胞增殖并诱导细胞凋亡。癌症莱特。2007， 248， doi：10.1016/j.canlet.2006.08.006.

56.  Yj, C.; Cc, L.; Yc, H.; Jl, S.; Lm, T.; Jh, C.; Jf, L.; Ch, L.; Sl, F. Andrographolide Suppresses the Malignancy of Triple-Negative Breast Cancer by Reducing THOC1-Promoted Cancer Stem Cell Characteristics. Biochem. Pharmacol. 2022, 206, doi:10.1016/j.bcp.2022.115327.
56. Yj， C.;Cc, L.;Yc， H.;Jl， S.;Lm， T.;Jh， C.;Jf， L.;Ch， L.;Sl， F. Andrographolide 通过减少 THOC1 促进的癌症干细胞特性来抑制三阴性乳腺癌的恶性肿瘤。生化。药理学。2022， 206， doi：10.1016/j.bcp.2022.115327.

57.  Z, Y.; H, J.; X, Z.; X, L.; J, L. Ginsenoside Rg3 Promotes Cytotoxicity of Paclitaxel through Inhibiting NF-κB Signaling and Regulating Bax/Bcl-2 Expression on Triple-Negative Breast Cancer. Biomed. Pharmacother. Biomedecine Pharmacother. 2017, 89, doi:10.1016/j.biopha.2017.02.038.
57. Z， Y.;H， J.;X， Z.;X， L.;J， L. 人参皂苷 Rg3 通过抑制 NF-κB 信号传导和调节 Bax/Bcl-2 表达促进紫杉醇在三阴性乳腺癌中的细胞毒性。生物医学。药剂师。生物美地碱药剂。2017， 89， doi：10.1016/j.biopha.2017.02.038.

58.  J, J. Hedgehog Signaling Mechanism and Role in Cancer. Semin. Cancer Biol. 2022, 85, doi:10.1016/j.semcancer.2021.04.003.
58. J， J. Hedgehog 信号传导机制和在癌症中的作用。 精明。癌症生物学。2022， 85， doi：10.1016/j.semcancer.2021.04.003.

59.  Na, R.-D.G.; Á, L.M.; Ev, W. Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics. Cells 2019, 8, doi:10.3390/cells8040375.
59. 娜，R.-D.G.;Á， LM;Ev， W. Hedgehog 信号传导在乳腺癌中的作用：发病机制和治疗学。细胞2019， 8， doi：10.3390/cells8040375。

60.  M, L.; T, G.; J, L.; X, H.; Q, K.; Y, W.; C, F.; C, H. Curcumin Inhibits the Invasion and Metastasis of Triple Negative Breast Cancer via Hedgehog/Gli1 Signaling Pathway. J. Ethnopharmacol. 2022, 283, doi:10.1016/j.jep.2021.114689.
60. M， L.;T， G.;J， L.;X， H.;Q， K.;Y， W.;C， F.;C， H. Curcumin 通过 Hedgehog/Gli1 信号通路抑制三阴性乳腺癌的侵袭和转移。J. 民族药理学。2022， 283， doi：10.1016/j.jep.2021.114689.

61.  Jm, L.; Yd, Y.; Jf, L.; Jx, L.; Ll, L.; Zq, L.; Y, D.; Y, X.; H, Z. Pharmacological Mechanisms of Sinomenine in Anti-Inflammatory Immunity and Osteoprotection in Rheumatoid Arthritis: A Systematic Review. Phytomedicine Int. J. Phytother. Phytopharm. 2023, 121, doi:10.1016/j.phymed.2023.155114.
61. Jm， L.;Yd， Y.;Jf， L.;Jx， L.;Ll， L.;Zq， L.;Y， D.;Y， X.;H， Z. Sinomenine 在类风湿性关节炎抗炎免疫和骨保护中的药理机制：系统评价。植物医学 Int. J. Phytother.植物药剂。2023， 121， doi：10.1016/j.phymed.2023.155114.

62.  L, S.; D, L.; Y, Z.; J, H.; H, K.; Z, D.; X, W.; S, Z.; Y, Z.; X, X. Sinomenine Reduces Growth and Metastasis of Breast Cancer Cells and Improves the Survival of Tumor-Bearing Mice through Suppressing the SHh Pathway. Biomed. Pharmacother. Biomedecine Pharmacother. 2018, 98, doi:10.1016/j.biopha.2017.12.065.
62. L， S.;D， L.;Y， Z.;J， H.;H， K.;Z， D.;X， W.;S， Z.;Y， Z.;X， X. Sinomenine 通过抑制 SHh 通路减少乳腺癌细胞的生长和转移，提高荷瘤小鼠的存活率。生物医学。药剂师。生物美地碱药剂。2018， 98， doi：10.1016/j.biopha.2017.12.065.

63.  Carpenter, R.L.; Lo, H.-W. STAT3 Target Genes Relevant to Human Cancers. Cancers 2014, 6, 897–925, doi:10.3390/cancers6020897.
63. 卡彭特，RL;Lo， H.-W.STAT3 靶向与人类癌症相关的基因。癌症2014， 6， 897–925， doi：10.3390/cancers6020897。

64.  R, G.; Tl, B.; G, N.; H, Y.; S, M.; Ca, M.-C.; Ce, C.; R, F.; R, F.; S, P.; et al. Constitutive Activation of Stat3 by the Src and JAK Tyrosine Kinases Participates in Growth Regulation of Human Breast Carcinoma Cells. Oncogene 2001, 20, doi:10.1038/sj.onc.1204349.
64. R， G.;Tl， B.;G， N.;H， Y.;S，M.;Ca， M.-C.;Ce， C.;R， F.;R， F.;S， P.;Src 和 JAK 酪氨酸激酶对 Stat3 的组成型激活参与人乳腺癌细胞的生长调节。癌基因2001， 20， doi：10.1038/sj.onc.1204349。

65.  H, J.; H, K.; K, S.; Ys, K. A Sesquiterpenoid from Farfarae Flos Induces Apoptosis of MDA-MB-231 Human Breast Cancer Cells through Inhibition of JAK-STAT3 Signaling. Biomolecules 2019, 9, doi:10.3390/biom9070278.
65. H， J.;H， K.;K， S.;Ys， K.来自 Farfarae Flos 的倍半萜类化合物通过抑制 JAK-STAT3 信号传导诱导 MDA-MB-231 人乳腺癌细胞凋亡。生物分子2019， 9， doi：10.3390/biom9070278.

66.  Hj, B.; P, D.; Dy, K.; N, S.; Yh, J.; Jh, P.; Sj, K.; Ym, Y. Silibinin Downregulates MMP2 Expression via Jak2/STAT3 Pathway and Inhibits the Migration and Invasive Potential in MDA-MB-231 Cells. Oncol. Rep. 2017, 37, doi:10.3892/or.2017.5588.
66. Hj， B.;P， D.;戴，K.;N， S.;Yh， J.;Jh， P.;Sj, K.;Ym， Y. silibinin 通过 Jak2/STAT3 通路下调 MMP2 表达，并抑制 MDA-MB-231 细胞中的迁移和侵袭潜力。肿瘤代表2017， 37， doi：10.3892/or.2017.5588.

67.  Dy, K.; N, S.; Dh, K.; Yh, J.; Hg, L.; Ym, P.; Ym, Y. Salidroside Inhibits Migration, Invasion and Angiogenesis of MDA‑MB 231 TNBC Cells by Regulating EGFR/Jak2/STAT3 Signaling via MMP2. Int. J. Oncol. 2018, 53, doi:10.3892/ijo.2018.4430.
67. 戴，K.;N， S.;Dh， K.;Yh， J.;Hg， L.;Ym， P.;Ym， Y. 红景天苷通过 MMP2 调节 EGFR/Jak2/STAT3 信号传导，抑制 MDA-MB 231 TNBC 细胞的迁移、侵袭和血管生成。国际 J. Oncol。2018， 53， doi：10.3892/ijo.2018.4430.

68.  J, C.; K, S.; Ys, K. Sesquiterpene Lactones-Enriched Fraction of Inula Helenium L. Induces Apoptosis through Inhibition of Signal Transducers and Activators of Transcription 3 Signaling Pathway in MDA-MB-231 Breast Cancer Cells. Phytother. Res. PTR 2018, 32, doi:10.1002/ptr.6189.
68. J， C.;K， S.;Ys， K. Inula Helenium L. 富含倍半萜内酯的部分通过抑制 MDA-MB-231 乳腺癌细胞中信号转导和转录 3 信号通路的激活剂诱导细胞凋亡。植物学。Res. PTR2018， 32， doi：10.1002/ptr.6189.

69.  M, C.; Pp, R. Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases. Microbiol. Mol. Biol. Rev. MMBR 2011, 75, doi:10.1128/MMBR.00031-10.
69. M， C.;pp， r. MAPK 及其底物、MAPK 活化蛋白激酶的激活和功能。微生物学 Mol. Biol. Rev. MMBR2011， 75， doi：10.1128/MMBR.00031-10.

70.  X, W.; J, Y.; X, L.; D, L.; Y, L.; L, S.; X, J.; X, Y.; Y, W.; L, C.; et al. PSMG2-Controlled Proteasome-Autophagy Balance Mediates the Tolerance for MEK-Targeted Therapy in Triple-Negative Breast Cancer. Cell Rep. Med. 2022, 3, doi:10.1016/j.xcrm.2022.100741.
70. X，W.;J， Y.;X， L.;D， L.;Y， L.;L， S.;X， J.;X， Y.;Y， W.;L， C.;PSMG2 控制的蛋白酶体-自噬平衡介导三阴性乳腺癌对 MEK 靶向治疗的耐受性。Cell Rep. Med.2022， 3， doi：10.1016/j.xcrm.2022.100741.

71.  B, P.; R, H.; Q, X.; Y, Y.; Q, H.; H, H.; X, L.; J, L. Ginsenoside 20(S)-Protopanaxadiol Inhibits Triple-Negative Breast Cancer Metastasis in Vivo by Targeting EGFR-Mediated MAPK Pathway. Pharmacol. Res. 2019, 142, doi:10.1016/j.phrs.2019.02.003.
71. B，P.;R， H.;Q， X.;Y， Y.;Q， H.;H， H.;X， L.;J， L. 人参皂甙 20（S）-Protopanaxadiol 通过靶向 EGFR 介导的 MAPK 通路在体内抑制三阴性乳腺癌转移。药理学研究2019， 142， doi：10.1016/j.phrs.2019.02.003.

72.  S, K.; D, Y.; Y, J.; J, Y.; Sw, K.; Sj, N.; Je, L. Berberine Down-Regulates IL-8 Expression through Inhibition of the EGFR/MEK/ERK Pathway in Triple-Negative Breast Cancer Cells. Phytomedicine Int. J. Phytother. Phytopharm. 2018, 50, doi:10.1016/j.phymed.2018.08.004.
72. S， K.;D， Y.;Y， J.;J， Y.;斯威，K.;Sj， N.;Je， L. 小檗碱通过抑制三阴性乳腺癌细胞中的 EGFR/MEK/ERK 通路下调 IL-8 表达。植物医学 Int. J. Phytother.植物药剂。2018， 50， doi：10.1016/j.phymed.2018.08.004.

73.  Xy, M.; Jn, Z.; Wy, J.; B, L.; Mn, W.; Ty, Z.; Ll, J. Scutellarin Suppresses Triple-Negative Breast Cancer Metastasis by Inhibiting TNFα-Induced Vascular Endothelial Barrier Breakdown. Acta Pharmacol. Sin. 2022, 43, doi:10.1038/s41401-022-00873-y.
73. Xy， M.;Jn， Z.;怀俄明州 J.;B，L.;明尼苏达州，W.;泰，Z.;Ll， J. Scutellarin 通过抑制 TNFα 诱导的血管内皮屏障破坏来抑制三阴性乳腺癌转移。药理学杂志。罪。2022， 43， doi：10.1038/s41401-022-00873-y.

74.  Sun, Y.; Zou, M.; Hu, C.; Qin, Y.; Song, X.; Lu, N.; Guo, Q. Wogonoside Induces Autophagy in MDA-MB-231 Cells by Regulating MAPK-mTOR Pathway. Food Chem. Toxicol. 2013, 51, 53–60, doi:10.1016/j.fct.2012.09.012.
74. 孙 Y.;邹 M.;胡 C.;秦 Y.;宋，X.;卢，N.;Guo， Q. Wogonoside 通过调节 MAPK-mTOR 通路诱导 MDA-MB-231 细胞自噬。食品化学毒理学。2013， 51， 53–60， doi：10.1016/j.fct.2012.09.012.

75.  S, M.; X, L.; L, Z.; Y, W.; L, S.; S, Y.; M, C.; Y, L. Chinese Medicine Formula “Baipuhuang Keli” Inhibits Triple-Negative Breast Cancer by Hindering DNA Damage Repair via MAPK/ERK Pathway. J. Ethnopharmacol. 2023, 304, doi:10.1016/j.jep.2022.116077.
75. S，M.;X， L.;L， Z.;Y， W.;L， S.;S， Y.;M， C.;Y， L. 中药方剂“百普黄可礼”通过 MAPK/ERK 通路阻碍 DNA 损伤修复，从而抑制三阴性乳腺癌。J. 民族药理学。2023， 304， doi：10.1016/j.jep.2022.116077.

76.  H, X.; L, L.; L, Q.; J, T.; X, S.; X, L.; K, X. Atractylenolide-1 Affects Glycolysis/Gluconeogenesis by Downregulating the Expression of TPI1 and GPI to Inhibit the Proliferation and Invasion of Human Triple-Negative Breast Cancer Cells. Phytother. Res. PTR 2023, 37, doi:10.1002/ptr.7661.
76. H， X.;L， L.;L， Q.;J， T.;X， S.;X， L.;K， X. Atractylenolide-1 通过下调 TPI1 和 GPI 的表达来抑制人三阴性乳腺癌细胞的增殖和侵袭，从而影响糖酵解/糖异生。植物学。Res. PTR2023， 37， doi：10.1002/ptr.7661.

77.  J, L.; S, L.; Y, H.; R, S.; T, S.; K, N.; P, H.; W, K.; Rk, J.; D, F.; et al. PDGF-D Improves Drug Delivery and Efficacy via Vascular Normalization, but Promotes Lymphatic Metastasis by Activating CXCR4 in Breast Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2011, 17, doi:10.1158/1078-0432.CCR-10-2456.
77. J， L.;S， L.;Y， H.;R， S.;T， S.;K， N.;P， H.;W，K.;Rk， J.;D， F.;PDGF-D 通过血管正常化改善药物递送和疗效，但通过激活乳腺癌中的 CXCR4 促进淋巴转移。克林。癌症研究 Off. J. Am. Assoc. Cancer Res.2011， 17， doi：10.1158/1078-0432.CCR-10-2456.

78.  Tieng, F.Y.F.; Latifah, S.Y.; Md Hashim, N.F.; Khaza’ai, H.; Ahmat, N.; Gopalsamy, B.; Wibowo, A. Ampelopsin E Reduces the Invasiveness of the Triple Negative Breast Cancer Cell Line, MDA-MB-231. Molecules 2019, 24, 2619, doi:10.3390/molecules24142619.
78. Tieng， F.Y.F.;拉蒂法，S.Y.;Md Hashim，NF;Khaza'ai， H.;艾哈迈特，N.;戈帕尔萨米，B.;Wibowo， A. Ampelopsin E 降低三阴性乳腺癌细胞系 MDA-MB-231 的侵袭性。分子2019， 24， 2619， doi：10.3390/molecules24142619.

79.  X, L.; K, W.; Y, R.; L, Z.; Xj, T.; Hm, Z.; Cq, Z.; Pj, L.; Jm, Z.; Jj, H. MAPK Signaling Mediates Sinomenine Hydrochloride-Induced Human Breast Cancer Cell Death via Both Reactive Oxygen Species-Dependent and -Independent Pathways: An in Vitro and in Vivo Study. Cell Death Dis. 2014, 5, doi:10.1038/cddis.2014.321.
79. X， L.;K， W.;Y， R.;L， Z.;Xj, T.;嗯，Z.;Cq， Z.;Pj, L.;Jm， Z.;Jj， H. MAPK 信号传导通过活性氧依赖性和非依赖性途径介导盐酸青青门碱诱导的人乳腺癌细胞死亡：体外和体内研究。细胞死亡 Dis.2014， 5， doi：10.1038/cddis.2014.321.

80.  Lang, S.J.; Schmiech, M.; Hafner, S.; Paetz, C.; Werner, K.; El Gaafary, M.; Schmidt, C.Q.; Syrovets, T.; Simmet, T. Chrysosplenol d, a Flavonol from Artemisia Annua, Induces ERK1/2-Mediated Apoptosis in Triple Negative Human Breast Cancer Cells. Int. J. Mol. Sci. 2020, 21, 4090, doi:10.3390/ijms21114090.
80. 朗，SJ;施米赫，M.;哈夫纳，S.;帕茨，C.;维尔纳，K.;埃尔加法里，M.;施密特，C.Q.;Syrovets， T.;Simmet， T. Chrysosplenol d，一种来自青蒿的黄酮醇，在三阴性人乳腺癌细胞中诱导 ERK1/2 介导的细胞凋亡。国际分子科学杂志2020， 21， 4090， doi：10.3390/ijms21114090.

81.  X, C.; Jr, C.-R. Endoplasmic Reticulum Stress Signals in the Tumour and Its Microenvironment. Nat. Rev. Cancer 2021, 21, doi:10.1038/s41568-020-00312-2.
81. X， C.;Jr， C.-R.肿瘤及其微环境中的内质网应激信号。癌症2021， 21， doi：10.1038/s41568-020-00312-2。

82.  D, X.; Z, L.; Mx, L.; Yj, F.; W, Z.; Y, W.; Jh, T. Endoplasmic Reticulum Stress Targeted Therapy for Breast Cancer. Cell Commun. Signal. CCS 2022, 20, doi:10.1186/s12964-022-00964-7.
82. D， X.;Z，L.;Mx， L.;Yj， F.;W， Z.;Y， W.;Jh， T. 乳腺癌的内质网应激靶向治疗。细胞通讯。信号。采石学报2022， 20， doi：10.1186/s12964-022-00964-7.

83.  Xh, L.; Xr, H.; Yy, Z.; Hy, Z.; Wx, Z.; St, J.; Q, Z.; Pp, L.; Sy, H. Taraxacum Mongolicum Extract Induced Endoplasmic Reticulum Stress Associated-Apoptosis in Triple-Negative Breast Cancer Cells. J. Ethnopharmacol. 2017, 206, doi:10.1016/j.jep.2017.04.025.
83. Xh， L.;Xr， H.;Yy， Z.;海，Z.;Wx， Z.;圣 J.;Q， Z.;Pp, L.;Sy， H. taraxacum mongolicum 提取物诱导三阴性乳腺癌细胞内质网应激相关细胞凋亡。J. 民族药理学。2017， 206， doi：10.1016/j.jep.2017.04.025.

84.  Jm, S.; Ll, B.; Dm, Z.; A, Y.; Zq, Y.; Wl, H.; Js, L.; Y, L.; Dy, F.; Wc, Y. Saxifragifolin D Induces the Interplay between Apoptosis and Autophagy in Breast Cancer Cells through ROS-Dependent Endoplasmic Reticulum Stress. Biochem. Pharmacol. 2013, 85, doi:10.1016/j.bcp.2013.01.009.
84. Jm， S.;LL，B.;Dm， Z.;A， Y.;Zq， Y.;Wl， H.;Js， L.;Y， L.;Dy， F.;Wc， Y. Saxifragifolin D 通过 ROS 依赖性内质网应激诱导乳腺癌细胞凋亡和自噬之间的相互作用。生化。药理学。2013， 85， doi：10.1016/j.bcp.2013.01.009.

85.  Y, J.; Dtn, H.; Ks, H. Ginsenoside Rh1 Inhibits Tumor Growth in MDA-MB-231 Breast Cancer Cells via Mitochondrial ROS and ER Stress-Mediated Signaling Pathway. Arch. Pharm. Res. 2022, 45, doi:10.1007/s12272-022-01377-3.
85. Y， J.;Dtn， H.;Ks， H. Ginsenoside Rh1 通过线粒体 ROS 和 ER 应激介导的信号通路抑制 MDA-MB-231 乳腺癌细胞中的肿瘤生长。Arch. Pharm. Res.2022， 45， doi：10.1007/s12272-022-01377-3.

86.  Bj, T.; Gn, C. Role of Oxidative Stress, Endoplasmic Reticulum Stress and ERK Activation in Triptolide-Induced Apoptosis. Int. J. Oncol. 2013, 42, doi:10.3892/ijo.2013.1843.
86. Bj， T.;Gn， C. 氧化应激、内质网应激和 ERK 激活在雷公藤内酯诱导的细胞凋亡中的作用。国际 J. Oncol。2013， 42， doi：10.3892/ijo.2013.1843.

87.  Ma, H.; E, A.; J, L.; Jf, B.; Nj, R.; Cs, Z. Putative Mammalian Taste Receptors: A Class of Taste-Specific GPCRs with Distinct Topographic Selectivity. Cell 1999, 96, doi:10.1016/s0092-8674(00)80658-3.
87. 马，H.;E， A.;J， L.;Jf， B.;新泽西州，R.;Cs， Z. 推定的哺乳动物味觉受体：一类具有不同地形选择性的味觉特异性 GPCR。细胞1999， 96， doi：10.1016/s0092-8674（00）80658-3。

88.  Da, D.; Wc, W.; El, M.; Ks, R.; Rm, S.; Ss, A.; Js, S.; Sb, L. Bitter Taste Receptors on Airway Smooth Muscle Bronchodilate by Localized Calcium Signaling and Reverse Obstruction. Nat. Med. 2010, 16, doi:10.1038/nm.2237.
88. 达，D.;Wc， W.;埃尔，M.;Ks, R.;Rm， S.;Ss， A.;Js， S.;Sb， L. 气道平滑肌支气管上的苦味受体通过局部钙信号传导和反向阻塞进行扩张。Nat. Med.2010， 16， doi：10.1038/nm.2237.

89.  Avau, B.; Rotondo, A.; Thijs, T.; Andrews, C.N.; Janssen, P.; Tack, J.; Depoortere, I. Targeting Extra-Oral Bitter Taste Receptors Modulates Gastrointestinal Motility with Effects on Satiation. Sci. Rep. 2015, 5, 15985, doi:10.1038/srep15985.
89. 阿沃，B.;罗通多，A.;蒂斯，T.;安德鲁斯，CN;詹森，P.;塔克，J.;Depoortere， I. 靶向口腔外苦味受体调节胃肠蠕动，对饱腹感有影响。科学代表2015， 5， 15985， doi：10.1038/srep15985.

90.  Kinnamon, S.C. Taste Receptor Signalling - from Tongues to Lungs. Acta Physiol. Oxf. Engl. 2012, 204, 158–168, doi:10.1111/j.1748-1716.2011.02308.x.
90. Kinnamon， SC 味觉受体信号 - 从舌头到肺。 物理学杂志 Oxf. Engl.2012， 204， 158–168， doi：10.1111/j.1748-1716.2011.02308.x.

91.  Z, Z.; Z, Z.; R, M.; E, L. The Transduction Channel TRPM5 Is Gated by Intracellular Calcium in Taste Cells. J. Neurosci. Off. J. Soc. Neurosci. 2007, 27, doi:10.1523/JNEUROSCI.4973-06.2007.
91. Z， Z.;Z， Z.;R，M.;E， L.转导通道 TRPM5 受味觉细胞中细胞内钙的控制。J. 神经科学。Off. J. Soc. 神经科学。2007， 27， doi：10.1523/JNEUROSCI.4973-06.2007.

92.  Rf, M. Molecular Mechanisms of Bitter and Sweet Taste Transduction. J. Biol. Chem. 2002, 277, doi:10.1074/jbc.R100054200.
92. Rf， M. 苦味和甜味转导的分子机制。 J. Biol. 化学。2002， 277， doi：10.1074/jbc.R100054200。

93.  A, J.; R, H.; Jd, U.; Rp, B.; P, C. Bitter Taste Receptors: Novel Insights into the Biochemistry and Pharmacology. Int. J. Biochem. Cell Biol. 2016, 77, doi:10.1016/j.biocel.2016.03.005.
93. A，J.;R， H.;Jd，美国;Rp， B.;P， C. 苦味受体：对生物化学和药理学的新见解。国际生物化学杂志。细胞生物学。2016， 77， doi：10.1016/j.biocel.2016.03.005.

94.  Hl, R.; Sj, C. Ca2+ Signalling Checkpoints in Cancer: Remodelling Ca2+ for Cancer Cell Proliferation and Survival. Nat. Rev. Cancer 2008, 8, doi:10.1038/nrc2374.
94. 赫尔，R.;SJ， C. 癌症中的 Ca2+ 信号检查点：重塑 Ca2+ 促进癌细胞增殖和存活。癌症2008， 8， doi：10.1038/nrc2374。

95.  Mm, G.; C, M.; U, D.; S, S.; P, S.; Gh, W.; Gm, H. Expression of the Bitter Receptor T2R38 in Pancreatic Cancer: Localization in Lipid Droplets and Activation by a Bacteria-Derived Quorum-Sensing Molecule. Oncotarget 2016, 7, doi:10.18632/oncotarget.7206.
95. 毫米，G.;C， M.;U， D.;S， S.;P， S.;Gh， W.;Gm， H. 苦味受体 T2R38 在胰腺癌中的表达：在脂滴中的定位和细菌来源的群体感应分子的激活。肿瘤目标2016， 7， doi：10.18632/oncotarget.7206。

96.  N, S.; R, C.; Rp, B.; P, C. Differential Expression of Bitter Taste Receptors in Non-Cancerous Breast Epithelial and Breast Cancer Cells. Biochem. Biophys. Res. Commun. 2014, 446, doi:10.1016/j.bbrc.2014.02.140.
96. N， S.;R， C.;Rp， B.;P，C. 非癌性乳腺癌上皮细胞和乳腺癌细胞中苦味受体的差异表达。生化。生物物理学。Res. Commun.2014， 446， doi：10.1016/j.bbrc.2014.02.140.

97.  N, S.; Fa, S.; Y, M.; P, C. Chemosensory Bitter Taste Receptors T2R4 and T2R14 Activation Attenuates Proliferation and Migration of Breast Cancer Cells. Mol. Cell. Biochem. 2020, 465, doi:10.1007/s11010-019-03679-5.
97. N， S.;法，S.;Y， M.;P， C. 化学感应苦味受体 T2R4 和 T2R14 激活减弱乳腺癌细胞的增殖和迁移。分子细胞。生化。2020， 465， doi：10.1007/s11010-019-03679-5.

98.  T, V.; Ad, G.; P, A. Targeting ER Stress Induced Apoptosis and Inflammation in Cancer. Cancer Lett. 2013, 332, doi:10.1016/j.canlet.2010.07.016.
98. T， V.;广告，G.;P， A. 靶向 ER 应激诱导的癌症细胞凋亡和炎症。癌症莱特。2013， 332， doi：10.1016/j.canlet.2010.07.016.

99.  R, K.; M, E.; K, T.; S, M. Role of the Unfolded Protein Response in Cell Death. Apoptosis Int. J. Program. Cell Death 2006, 11, doi:10.1007/s10495-005-3088-0.
99. R， K.;M， E.;K，T.;S， M. 未折叠蛋白反应在细胞死亡中的作用。细胞凋亡国际杂志计划。细胞死亡2006， 11， doi：10.1007/s10495-005-3088-0.

100.  S, O.; M, M. Roles of CHOP/GADD153 in Endoplasmic Reticulum Stress. Cell Death Differ. 2004, 11, doi:10.1038/sj.cdd.4401373.
100. S， O.;M， M. CHOP/GADD153 在内质网应激中的作用。细胞死亡不同。2004， 11， doi：10.1038/sj.cdd.4401373.

101.  Carey, R.M.; McMahon, D.B.; Miller, Z.A.; Kim, T.; Rajasekaran, K.; Gopallawa, I.; Newman, J.G.; Basu, D.; Nead, K.T.; White, E.A.; et al. T2R Bitter Taste Receptors Regulate Apoptosis and May Be Associated with Survival in Head and Neck Squamous Cell Carcinoma. Mol. Oncol. 2022, 16, 1474–1492, doi:10.1002/1878-0261.13131.
101. 凯里，RM;麦克马洪，D.B.;米勒，Z.A.;金 T.;拉贾塞卡兰，K.;戈帕拉瓦，I.;纽曼，J.G.;巴苏，D.;尼德，KT;怀特，EA;T2R 苦味受体调节细胞凋亡，可能与头颈部鳞状细胞癌的生存率有关。Mol. Oncol.2022， 16， 1474–1492， doi：10.1002/1878-0261.13131.

102.  Allbritton, N.L.; Oancea, E.; Kuhn, M.A.; Meyer, T. Source of Nuclear Calcium Signals. Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 12458–12462, doi:10.1073/pnas.91.26.12458.
102. 奥尔布里顿，NL;奥安查，E.;马萨诸塞州库恩;Meyer， T. 核钙信号的来源。美国国家科学院院刊1994， 91， 12458–12462， doi：10.1073/pnas.91.26.12458.

103.  Leite, M.F.; Thrower, E.C.; Echevarria, W.; Koulen, P.; Hirata, K.; Bennett, A.M.; Ehrlich, B.E.; Nathanson, M.H. Nuclear and Cytosolic Calcium Are Regulated Independently. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 2975–2980, doi:10.1073/pnas.0536590100.
103. 雷特，MF;Thrower， EC;Echevarria， W.;库伦，P.;平田，K.;贝内特，上午;埃利希，B.E.;Nathanson， MH 核钙和胞质钙独立调节。美国国家科学院院刊2003， 100， 2975–2980， doi：10.1073/pnas.0536590100.

104.  A, D.; O, S. el dein; E, M.; D, P.; G, K.; C, L.; C, B. Endoplasmic Reticulum Stress Induces Calcium-Dependent Permeability Transition, Mitochondrial Outer Membrane Permeabilization and Apoptosis. Oncogene 2008, 27, doi:10.1038/sj.onc.1210638.
104. A，D.;O， S. el dein;E， M.;D， P.;G，K.;C， L.;C， B. 内质网应激诱导钙依赖性通透性转变、线粒体外膜通透和细胞凋亡。癌基因2008， 27， doi：10.1038/sj.onc.1210638.

105.  C, D.; S, K.; S, S.; M, P.-C.; M, T.; N, H. Mitochondrial Calcium Regulation of Redox Signaling in Cancer. Cells 2020, 9, doi:10.3390/cells9020432.
105. C， D.;S， K.;S， S.;M， P.-C.;M， T.;N， H. 癌症中氧化还原信号传导的线粒体钙调节。细胞2020， 9， doi：10.3390/cells9020432。

106.  S, Y.; R, P.; I, S.; A, Z.; T, S.; L, S.; T, B.; Hu, S. Calpain-Mediated Cleavage of Atg5 Switches Autophagy to Apoptosis. Nat. Cell Biol. 2006, 8, doi:10.1038/ncb1482.
106. S， Y.;R， P.;I， S.;A， Z.;T， S.;L， S.;T，B.;胡， S. 钙蛋白酶介导的 Atg5 切割将自噬转变为细胞凋亡。Nat. 细胞生物学2006， 8， doi：10.1038/ncb1482.

107.  S, G.; T, Y.; L, S.; A, L.; T, Z.; Y, X.; W, J.; Q, Y.; L, Y.; L, L.; et al. Matrine, as a CaSR Agonist Promotes Intestinal GLP-1 Secretion and Improves Insulin Resistance in Diabetes Mellitus. Phytomedicine Int. J. Phytother. Phytopharm. 2021, 84, doi:10.1016/j.phymed.2021.153507.
107. S， G.;T， Y.;L， S.;A， L.;T， Z.;Y， X.;W， J.;Q， Y.;L， Y.;L， L.;等。Matrine 作为一种 CaSR 激动剂，可促进肠道 GLP-1 分泌并改善糖尿病患者的胰岛素抵抗。植物医学 Int. J. Phytother.植物药剂。2021， 84， doi：10.1016/j.phymed.2021.153507.

108.  Y, Y.; G, H.; Q, Z.; W, H.; M, W.; W, Z.; S, Z.; M, H.; X, W. Berberine Induces GLP-1 Secretion through Activation of Bitter Taste Receptor Pathways. Biochem. Pharmacol. 2015, 97, doi:10.1016/j.bcp.2015.07.012.
108. Y， Y.;G， H.;Q， Z.;W， H.;M， W.;W， Z.;S， Z.;M， H.;X， W. 小檗碱通过激活苦味受体通路诱导 GLP-1 分泌。生化。药理学。2015， 97， doi：10.1016/j.bcp.2015.07.012.

109.  K, N.; J, G.; B, B.; Y, P.; J, L.; L, L.; M, L.; L, D. Naringin as a Plant-Derived Bitter Tastant Promotes Proliferation of Cultured Human Airway Epithelial Cells via Activation of TAS2R Signaling. Phytomedicine Int. J. Phytother. Phytopharm. 2021, 84, doi:10.1016/j.phymed.2021.153491.
109. K， N.;J， G.;B，B.;Y， P.;J， L.;L， L.;M， L.;L， D. 柚皮苷作为植物来源的苦味物质，通过激活 TAS2R 信号传导促进培养的人气道上皮细胞的增殖。植物医学 Int. J. Phytother.植物药剂。2021， 84， doi：10.1016/j.phymed.2021.153491.

110.  Y, Z.; Z, J.; J, L.; Z, Z.; J, L.; X, C.; Z, Z.; P, L.; W, M. Berberine Activates Caspase-9/Cytochrome c-Mediated Apoptosis to Suppress Triple-Negative Breast Cancer Cells in Vitro and in Vivo. Biomed. Pharmacother. Biomedecine Pharmacother. 2017, 95, doi:10.1016/j.biopha.2017.08.045.
110. Y， Z.;Z， J.;J， L.;Z， Z.;J， L.;X， C.;Z， Z.;P， L.;W， M. 小檗碱激活 caspase-9/细胞色素 c 介导的细胞凋亡，在体外和体内抑制三阴性乳腺癌细胞。生物医学。药剂师。生物美地碱药剂。2017， 95， doi：10.1016/j.biopha.2017.08.045.

111.  Sm, A.-B.; Kh, A.-B.; Zm, A.-A.; Ny, A.-A.; Zr, A.-H.; Ss, A.-R. Cisplatin Induces Apoptosis Through the Endoplasmic Reticulum-Mediated, Calpain 1 Pathway in Triple-Negative Breast Cancer Cells. Clin. Breast Cancer 2017, 17, doi:10.1016/j.clbc.2016.12.001.
111. Sm，A.-B.;Kh， A.-B.;Zm，A.-A.;纽约，A.-A.;Zr， A.-H.;Ss， A.-R.顺铂通过内质网介导的三阴性乳腺癌细胞钙蛋白酶 1 通路诱导细胞凋亡。克林。乳腺癌2017， 17， doi：10.1016/j.clbc.2016.12.001.

112.  Kim, J.Y.; Lee, N.; Kim, Y.-J.; Cho, Y.; An, H.; Oh, E.; Cho, T.-M.; Sung, D.; Seo, J.H. Disulfiram Induces Anoikis and Suppresses Lung Colonization in Triple-Negative Breast Cancer via Calpain Activation. Cancer Lett. 2017, 386, 151–160, doi:10.1016/j.canlet.2016.11.022.
112. 金，JY;李，N.;金，YJ;赵 Y.;安，H.;哦，E.;Cho， T.-M.;宋 D.;Seo， JH Disulfiram 通过钙蛋白酶激活诱导三阴性乳腺癌的失巢凋亡并抑制肺定植。癌症莱特。2017， 386， 151–160， doi：10.1016/j.canlet.2016.11.022.

113.  J, G.; M, F.; S, P.; M, Z.; G, X.; X, L.; W, G.; Y, S.; X, W.; G, L.; et al. Small-Molecule RL71-Triggered Excessive Autophagic Cell Death as a Potential Therapeutic Strategy in Triple-Negative Breast Cancer. Cell Death Dis. 2017, 8, doi:10.1038/cddis.2017.444.
113. J， G.;M， F.;S， P.;M， Z.;G， X.;X， L.;W， G.;Y， S.;X， W.;G， L.;等。小分子 RL71 触发的过度自噬细胞死亡是三阴性乳腺癌的潜在治疗策略。细胞死亡 Dis.2017， 8， doi：10.1038/cddis.2017.444.

114.  D, H.; Ra, W. The Hallmarks of Cancer. Cell 2000, 100, doi:10.1016/s0092-8674(00)81683-9.
114. D，H.;拉，W.癌症的标志。细胞2000， 100， doi：10.1016/s0092-8674（00）81683-9。

115.  F, B.; A, G. Pathology of Triple Negative Breast Cancer. Semin. Cancer Biol. 2021, 72, doi:10.1016/j.semcancer.2020.06.005.
115. F，B.;A， G. 三阴性乳腺癌的病理学。精明。癌症生物学。2021， 72， doi：10.1016/j.semcancer.2020.06.005.

116.  Yw, L.; Tl, C.; Yr, S.; Cl, T.; Cc, C.; Hh, L.; Sh, T.; Sc, C.; Cc, W. Adjunctive Traditional Chinese Medicine Therapy Improves Survival in Patients with Advanced Breast Cancer: A Population-Based Study. Cancer 2014, 120, doi:10.1002/cncr.28579.
116. Yw， L.;Tl， C.;伊尔，S.;Cl， T.;Cc, C.;Hh， L.;Sh， T.;Sc， C.;Cc， W. 辅助中医治疗提高晚期乳腺癌患者的生存率：一项基于人群的研究。癌症2014， 120， doi：10.1002/cncr.28579.

117.  F, Q.; L, Z.; A, Z.; B, Z.; A, L.; Z, W.; J, H. The Advantages of Using Traditional Chinese Medicine as an Adjunctive Therapy in the Whole Course of Cancer Treatment Instead of Only Terminal Stage of Cancer. Biosci. Trends 2015, 9, doi:10.5582/bst.2015.01019.
117. F， Q.;L， Z.;A， Z.;B， Z.;A， L.;Z， W.;J， H.在癌症治疗的整个过程中使用中医作为辅助治疗的优势，而不仅仅是癌症的终末期。生物科学。趋势2015， 9， doi：10.5582/bst.2015.01019.

118.  Yang, F.; Dong, X.; Yin, X.; Wang, W.; You, L.; Ni, J. Radix Bupleuri: A Review of Traditional Uses, Botany, Phytochemistry, Pharmacology, and Toxicology. BioMed Res. Int. 2017, 2017, 7597596, doi:10.1155/2017/7597596.
118. 杨， F.;董 X.;尹 X.;王 W.;你，L.;Ni， J. 柴胡：传统用途、植物学、植物化学、药理学和毒理学综述。BioMed Res. Int.2017， 2017， 7597596， doi：10.1155/2017/7597596.

119.  Sm, S.; Rk, W. Chinese Medicine and Biomodulation in Cancer Patients--Part One. Curr. Oncol. Tor. Ont 2008, 15, doi:10.3747/co.2008.197.
119. Sm， S.;Rk， W. 癌症患者的中医和生物调节--第一部分。电流。Oncol.托尔。安大略报2008， 15， doi：10.3747/co.2008.197.

120.  Ag, A.; B, W.; Em, P.-W.; T, L.; C, W.; P, U.; V, T.; L, W.; S, S.; Eh, H.; et al. Discovery and Resupply of Pharmacologically Active Plant-Derived Natural Products: A Review. Biotechnol. Adv. 2015, 33, doi:10.1016/j.biotechadv.2015.08.001.
120. 阿格，A.;B， W.;Em， P.-W.;T， L.;C， W.;P， 美国;V， T.;L， W.;S， S.;嗯，H.;等。药理活性植物来源天然产物的发现和供应：综述。生物技术 Adv.2015， 33， doi：10.1016/j.biotechadv.2015.08.001.