Hepatocellular carcinoma (HCC) is a highly aggressive tumor with rapid propensity for extrahepatic metastasis, which critically limits long-term clinical benefits of conventional chemotherapeutics and decreases the overall survival rate of patients. Our previous reports have documented the anti-HCC potential and pharmacological safety of uttroside B (Utt-B). Herein, we illustrate the role of EGFR/ERK signaling axis and their downstream targets SREBP-1 and STAT-3, in the action mechanism of Utt-B. Further, the current study also demonstrates the strong anti-invasive and anti-metastatic properties of Utt-B against liver cancer. Pharmacological inhibition of EGFR/ERK axis led to the abrogation of Utt-B-mediated cytotoxicity and induction of apoptosis, in vitro. siRNA-mediated silencing of EGFR resulted in the attenuation of the cytotoxic, pro-apoptotic and anti-invasive effects of Utt-B, in vitro, thereby validating the regulatory role of EGFR in orchestrating the anti-HCC and anti-metastatic potential of Utt-B. In vivo studies confirmed that treatment with Utt-B mitigates the development of primary hepatic tumors in an orthotopic xenograft model and impedes the pulmonary metastasis of HCC in a murine metastasis model, via the down-regulation of EGFR/ERK axis. Taken together, the current findings attest to the exceptional therapeutic potential of Utt-B against primary and metastatic HCC and highlight its potential as a candidate drug to be evaluated in the clinics for the benefit of HCC patients having limited prognosis and therapeutic options.

Introduction: The continued exploration of natural resources holds great potential for identifying novel and effective anticancer compounds. In this study, we aim to analyze the anticancer potential of the methanol extract from the rhizome of the ethnomedicinal plant Corallocarpus epigaeus against skin cancer. Methods: A methanol extract of the rhizome (CME) was prepared by successive extraction using a polarity gradient of the dried powder. Anticancer potential of CME was assessed by MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) - cell viability assay. Antiproliferative activity of CME against skin cancer cells was confirmed by fluorescent microscopy and in vitro scratch assay. The cell death mechanism exhibited by CME was analysed by FACS (Fluorescence-Activated Cell Sorting) and Western blot analysis. Results: The MTT assay revealed a significant cytotoxic effect of CME against skin cancer cells, especially the melanoma skin cancer cell line (IC50 0.15 μg/mL), and its non-toxicity towards normal fibroblast cells. In vitro scratch assay and acridine orange/ethidium bromide staining confirmed the cytotoxic effect against the melanoma cell line, A375. FACS analysis of CME-treated A375 cells stained with FITC-Annexin V/PI revealed that the cytotoxic effect was mediated through apoptotic cell death. Additionally, immunoblot analysis revealed the activation of p53 and upregulation of the Bax protein, indicating the involvement of the p53-mediated apoptotic pathway. Discussion: The present study highlights the potent anticancer efficacy of a bioactive extract (CME) from Corallocarpus epigaeus against both melanoma and NMSC skin cancer cells, with preliminary evidence of apoptosis induction in melanoma. Ongoing work in our lab aims to isolate the active compound(s), characterize the phytochemicals, elucidate the molecular mechanisms underlying the anticancer activity, and explore the potential of CME as a topical chemotherapeutic agent for treating melanoma. Conclusion: Our study provides evidence for the potential of CME against skin cancer cells, particularly melanoma, and warrants further exploration of its chemotherapeutic efficacy against melanoma.

Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury, ultimately triggering chronic conditions, including fibrosis and cirrhosis, which may progress to hepatocellular carcinoma (HCC). Uttroside B (Utt-B), a phytosaponin isolated in our lab, has gained global recognition owing to its anti-HCC potential and is currently a United States FDA-designated ‘orphan drug’ against HCC. The present study highlights Utt-B as a propitious candidate drug against MASH and MASH-induced HCC. Methods: MASH and MASH-induced HCC were developed in C57BL/6J mice using two distinct murine models: a high-fat diet model and a streptozotocin-induced steatohepatitis-derived HCC model, followed by i.p. administration of Utt-B. Protein expression analysis was performed using real-time quantitative reverse transcription-PCR and immunoblotting, while H&E, Oil Red O, Sirius Red, and Masson’s Trichrome were utilized for staining cells/tissues. Nanostring n-Counter analysis was used to investigate the mechanism underlying the antifibrotic effects of Utt-B in MASH-induced HCC. Proliferation and apoptosis markers were also evaluated. Statistical analyses were conducted using R and GraphPad-Prism with significance set at p <0.05. Results: Utt-B ameliorated MASH-associated pathological features, including steatosis, hepatocyte ballooning, and inflammation (N = 6; non-alcoholic fatty liver disease activity score [NAS] <2, p <0.0001). Utt-B upregulated the expression of autophagy markers autophagy-related 7 (ATG-7), Beclin-1, and microtubule-associated protein 1A/1B-light chain (LC3-II), and downregulated the expression of α-smooth muscle actin (α-SMA), which indicates the activation of hepatic stellate cells. Utt-B also halted the progression of MASH to HCC by hindering development of fibrosis with simultaneous inhibition of proliferative signals and induction of apoptosis in murine models (N = 6; NAS <3, p <0.01). Conclusion: Our investigation revealed effective impedance of MASH and its concomitant progression to HCC by Utt-B. Given the lack of anti-MASH drugs, these findings establish Utt-B as a potent drug for treating MASH and MASH-induced HCC. Impact and implications: MASH, stage IV of non-alcoholic fatty liver disease, can lead to chronic conditions, including fibrosis and cirrhosis, elevating the risk of HCC. Impaired lipid metabolism, inflammation, inhibition of autophagy, and dysregulated collagen and extracellular matrix biosynthesis are key factors contributing to the advance of MASH to HCC. Our discovery of Utt-B, a phytosaponin that exhibits remarkable anti-HCC potential and is a United States FDA-designated orphan drug against HCC, has gained global recognition. The present study reveals Utt-B as a propitious candidate drug against MASH and MASH-induced HCC in a high-fat diet murine model and streptozotocin-induced steatohepatitis-derived HCC animal model, respectively.

The sustained exposure to aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus sp ., is one of the fundamental causes of hepatocellular carcinoma (HCC). We have previously documented the exceptional anti-HCC potential and pharmacological safety of uttroside B, a phytosaponin isolated in our lab (Utt-B). The current results indicate that Utt-B mitigates tumor development in mice that have been subjected to AFB1 exposure. Utt-B was found to be cytotoxic towards primary liver cancer cells cultured from mice bearing AFB1-induced liver tumors and the compound effectively prevented the formation of AfBO-DNA adducts in AFB1-induced liver tumors as well as primary liver cancer cells. In vitro studies revealed that treatment with Utt-B resulted in the induction of damage associated molecular patterns such as, ROS, HSP70 and inflammatory cytokines, IL-1β and CXCL-10, suggesting the potential of Utt-B in triggering immunogenic cell death. Mechanistically, treatment with Utt-B enhances the antigen presentation potential, causes blockade of the major immune checkpoint molecules, namely, CTLA-4, PD-1, TIM-3, LAG-3 and TOX, and potentiates immunogenic apoptosis in the hepatic tumor microenvironment of mice pre-exposed to AFB1 via the activation of Zap70/Lck/GRZB signaling axis. Interestingly, it was also observed that Utt-B could abrogate the mutations induced by AFB1 in a concentration dependent manner. Taken together, the findings of the current study attest Utt-B as a propitious drug candidate against HCC. ### Competing Interest Statement The authors have declared no competing interest. * AFB1 : Aflatoxin B1; AFP : Alpha Fetoprotein; Utt-B : Uttroside B; HCC : Hepatocellular carcinoma; H&E staining : Haematoxylin and Eosin staining; H : hour; LFT : Liver Function Test; RFT : Renal Function Test; PARP : Poly adenosine diphosphate-ribose polymerase; ki67 : Marker of proliferation; PCNA : Proliferating cell nuclear antigen; PBS : Phosphate buffered saline; IP : Intra-peritoneal; GAPDH : Glyceraldehyde 3-phosphate dehydrogenase; FBS : Fetal bovine serum, TNF-α : Tumor necrosis factor alpha; IFN-ꝩ : Interferon gamma; MCP-1 : Monocyte Chemoattractant protein-1; SCD-1 : Stearoyl CoA desaturase; SREBP 1-c : sterol regulatory element binding transcription factor; TME : Tumor microenvironment, DC : dendritic cells; ICD : Immunogenic cell death. Department of Biotechnology, https://ror.org/03tjsyq23 Department of Science and Technology, https://ror.org/0101xrq71 University Grants Commission, https://ror.org/04p800546

The continuous increase in the number of cancer cases and rates of cancer-related mortality globally is a highly concerning issue. Drug-induced toxicity, drastic side effects and chemoresistance associated with conventional chemotherapeutics warrant the need for novel, efficient, and safer alternative therapeutic approaches to help combat cancer. Plants are a rich source of bioactive compounds with potential anti-cancer activity. Extensive research on the chemotherapeutic efficacy of various plant-derived bioactive compounds is being carried out across the world. While cancer chemoprevention approaches prevent, delay, or suppress tumor incidence, chemosensitization approaches employ synthetic or natural bioactive agents to enhance the efficacy of conventional chemotherapeutic drugs at lower doses. Numerous studies have documented the efficiency of both of these approaches in managing different types of cancer. The scope of this chapter encompasses a comprehensive analysis of the current status and limitations of conventional chemotherapeutics and the clinical relevance of chemoprevention and chemosensitization strategies for the effective management of cancer, with a special emphasis on the potency of some of the major phytochemicals that are extensively being studied as novel chemopreventives and/or chemosensitizers, globally. Besides, an overview of the underlying mechanisms of action of these phytochemicals in regulating the signal transduction events associated with cancer progression, has also been discussed in this chapter.

INTRODUCTION:Sorafenib (Sor) is the first-line treatment option in clinics for treating advanced unresectable hepatocellular carcinoma (HCC). However, acquired chemoresistance and adverse side effects associated with Sor monotherapy limit its clinical benefits. We have previously reported the exceptional anti-HCC potential of uttroside B (Utt-B), a furostanol saponin isolated in our lab from Solanum nigrum Linn. leaves. The current study has evaluated the supremacy of a combinatorial regimen of Sor and Utt-B over Sor monotherapy. METHODS:MTT assay was used for In vitro cytotoxicity studies. A clonogenic assay was conducted to assess the anti-proliferative effect of the combination. Annexin V/PI staining, confocal microscopy, FACS cell cycle analysis, and Western blotting experiments were performed to validate the pro-apoptotic potential of the combination in HepG2 and Huh7 cell lines. Pharmacological safety evaluation was performed in Swiss albino mice. RESULTS:Our results indicate that Utt-B augments Sor-induced cytotoxicity in HepG2 and Huh7 cells. The combination inhibits the proliferation of liver cancer cells by inducing apoptosis through activation of the caspases 7 and 3, leading to PARP cleavage. Furthermore, the combination does not induce any acute toxicity in vivo, even at a dose five times that of the effective therapeutic dose. CONCLUSION:Our results highlight the potential of Utt-B as an effective chemosensitizer, which can augment the efficacy of Sor against HCC and circumvent Sor-induced toxic side effects. Moreover, this is the first and only report to date on the chemosensitizing potential of Utt-B and the only report that demonstrates the therapeutic efficacy and pharmacological safety of a novel combinatorial regimen involving Utt-B and Sor for combating HCC.

Introduction: Non-alcoholic steatohepatitis (NASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury. NASH can lead to chronic conditions like fibrosis and cirrhosis, and has an elevated risk of progressing to hepatocellular carcinoma (HCC). Currently there are no FDA-approved drugs for the treatment of NASH. Objectives: Our discovery of Uttroside B (Utt-B), a phytosaponin isolated from Solanum nigrum Linn., which exhibits remarkable anti-HCC potential, has gained global recognition and is currently a US-FDA-designated orphan drug against HCC. The present study highlights Utt-B as an anti-NASH molecule, by utilizing a High-Fat-Diet murine model, and as an inhibitor to the progression of NASH to HCC, using a streptozotocin-induced steatohepatitis-derived HCC animal model, thereby warranting its further validation as a propitious candidate drug molecule against NASH and NASH-induced HCC. Methods: High fat diet-induced NASH and streptozotocin-induced steatohepatitis-derived HCC were developed in C57BL/6 mice. Utt-B was administered intraperitoneally. q-PCR, immunoblotting and staining techniques such as Haematoxylin and eosin, Oil Red O, Sirius Red and Massons Trichrome, were performed to assess the therapeutic potency of Utt-B against NASH. Nanostring n-Counter analysis was conducted to verify the anti-fibrotic potential of Utt-B in NASH-induced HCC mouse model. Results: Utt-B ameliorates the pathological features such as, steatosis, hepatocyte ballooning and inflammation associated with NASH. Utt-B up-regulates the expression of autophagy markers ATG7, Beclin-1 and LC-III and down-regulates the expression of α-SMA, the indicator protein for the activation of hepatic stellate cells. Utt-B hinders the development of fibrosis and halts the progression of NASH to HCC in NASH-induced HCC mouse model. Conclusion: Our investigation reveals that Utt-B effectively alleviates NASH and abrogates its progression to HCC. As no treatment options are currently available against NASH, our findings are very relevant and strengthen the prospect of developing Utt-B as a potent drug for the treatment of NASH and NASH-induced HCC. Keywords: Uttroside B; NASH; HCC; NAFLD; Lipogenesis; Fibrogenesis ### Competing Interest Statement The authors have declared no competing interest.

The Transcription factor II B (TFIIB)‑related factor 2 (BRF2) containing TFIIIB complex recruits RNA polymerase III multi-subunit complex to selective gene promoters that altogether are responsible for synthesizing a variety of small non-coding RNAs, including a special type of selenocysteine tRNA (tRNASec), micro-RNA (miRNA), and other regulatory RNAs. BRF2 has been identified as a potential oncogene that promotes cancer cell survival under oxidative stress through its genetic activation. The structure of the BRF2 protein was modeled using the Robetta server, refined, and validated using the Ramachandran plot. A virtual approach utilizing molecular docking was used to screen a natural compound library to determine potential compounds that can interact with the molecular pin motif of the BRF2 protein using Maestro (Schrodinger). Subsequent molecular dynamics simulation studies of the top four ligands that exhibited low glide scores were performed using GROMACS. The findings derived from the simulations, in conjunction with the exploration of hydrogen bonding patterns, evaluation of the free energy landscape, and thorough analysis of residue decomposition, collectively converged to emphasize the robust interaction characteristics exhibited by Ligand 366 (Deacetyl lanatoside C) and ligand 336 (Neogitogenin)-with the BRF2 protein. These natural compounds may be potential inhibitors of BRF2, which could modulate the regulation of selenoprotein synthesis in cancer cells. Targeting BRF2 using these promising compounds may offer a new therapeutic approach to sensitize cancer cells to ferroptosis and apoptosis.Communicated by Ramaswamy H. Sarma.

Introduction and Aim: The incidence of non-alcoholic fatty liver disease is increasing steadily across the global population. NAFLD may progress to the more serious non-alcoholic steatohepatitis (NASH), a condition that can subsequently advance to fibrosis, cirrhosis, and in many cases, to hepatocellular carcinoma (HCC). There are currently no drugs approved by the FDA for the treatment of NAFLD. We previously reported the remarkable therapeutic potency of Utt-B, a saponin isolated in our lab, from the leaves of Solanum nigrum Linn (S. nigrum), against hepatocellular carcinoma (HCC). In the current study, we have investigated the therapeutic efficacy of Utt-B against NAFLD, which eventually leads to NASH. Materials and Methods: HepG2 cells were used for in vitro experiments. MTT assay, Oil Red O staining and Immunoblotting were used to evaluate the hepatoprotective and therapeutic effects of Utt-B against NAFLD. Results: Utt-B treatment effectively reduced lipid droplet accumulation within HepG2 cells, demonstrating its potential in mitigating fat deposition associated with NAFLD. Utt-B activated AMPK signaling, leading to the down-regulation of FASN, a key enzyme regulating lipogenesis, suggesting its ability to modulate pathways involved in lipid metabolism. Conclusion: Our results highlight Utt-B as a promising therapeutic agent for metabolic liver disorders, including NAFLD and NASH, warranting further exploration of the molecule in clinical settings.

Somatic mutations in JAK2 have been reported to cause myeloproliferative neoplasms, autoimmune disorders, rheumatoid arthritis, and inflammation. JAK2 protein with PDB id 3FUP was selected for docking analysis via cross-docking. Molecular docking of JAK2 with ATP and crystal ligand revealed their binding affinities and interactions. 3D QSAR models with R2=0.997 and Q2=0.984 having high stability and predictivity were generated. The biological activity of the hit compound obtained from virtual screening, LAS 26879206, was predicted to be 4.21 using the 3D QSAR model. Modification of LAS 26879206 utilizing 3D QSAR contours for modulating its JAK2 inhibitory potential yielded two novel inhibitors with a 2-aminopyrimidine core - ACP1 and ACPM1. Molecular docking, molecular dynamics simulations, and ADMET analysis indicated improvements in the efficiency of these compounds compared to the hit compound. Synthesis of these compounds was carried out using a two-step reaction- first Buchwald - Hartwig coupling reaction to yield an intermediate ACB1 which was then coupled with appropriate boronic acids via Suzuki reaction to get ACP1 and ACPM1. The effects of these designed compounds as anticancer agents were analyzed in hCT-116 (human colorectal carcinoma), HeLa (cervical carcinoma), A549 (human lung adenocarcinoma), and A375 (human melanoma) cell lines. ACPM1 was found to be active in all the cell lines with a pIC50 of 5 which was in concordance with the in silico studies. Western blot analysis validated the JAK2 inhibitory property of ACPM1 which can be further ensured by in vivo studies. Identification of Janus Kinase through molecular modelling, modification using 3D QSAR, docking, MD simulations, ADMET analysis, DFT studies, synthesis and in vitro studies of novel molecules- Elucidating the utilization of JAK2 inhibitors for solid cancers. image

Phytochemicals, the bioactive compounds derived from plants, play a significant role in modulating pathways leading to cancer and inflammation, rendering themselves promising candidates for therapeutic interventions. This review explores the multifaceted potential of various phytochemicals in modulating key mechanisms involved in the development and progression of cancer and inflammation. The diverse array of phytochemicals discussed here encompasses polyphenols, flavonoids, alkaloids, terpenoids, and many others, each with distinct molecular targets and modes of action. This review is an attempt to elucidate and correlate the regulatory role of phytochemicals on cellular signaling pathways implicated in oncogenesis and inflammatory responses, highlighting the significance and potential of phytochemical-based therapies for cancer prevention and treatment, as well as for managing inflammatory conditions. By exploring the promising potential of phytochemical-based remedies for cancer prevention, treatment, and inflammatory conditions and emphasizing their diverse roles in modulating critical regulatory mechanisms, this review addresses the current research landscape, challenges, and future directions in utilizing phytochemicals as effective agents against cancer and inflammation.

Our prior investigation has confirmed that the anti-hepatocellular carcinoma activity of the plant saponin, specifically Uttroside B (Utt-B), derived from the leaves of Solanum nigrum Linn. This study concentrated on formulating a novel biocompatible nanocarrier utilizing Extracellular vesicles (EVs) to enhance the delivery of plant saponin into cells. The physicochemical attributes of Extracellular Vesicles/UttrosideB (EVs/Utt-B) were comprehensively characterized through techniques such as Transmission Electron Microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). Despite the promising therapeutic potential of this uttroside B, mechanistic know-how about its entry into cells is still in its infancy. Our research sheds light on the extracellular vesicle-mediated mechanism facilitating the entry of the saponin into cells, a phenomenon confirmed through the use of by confocal microscopy. We further analysed drug-releasing kinetics and simulated the Pharmacokinetics by PBPK modelling. The simulated pharmacokinetics revealed the bioavailability of Uttroside-B in oral administration against intravenous administration.

Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, accounting for 85-90% of liver cancer cases and is a leading cause of cancer-related mortality worldwide. The major risk factors for HCC include hepatitis C and B viral infections, along with chronic liver diseases, such as cirrhosis, fibrosis, and non-alcoholic steatohepatitis associated with metabolic syndrome. Despite the advancements in modern medicine, there is a continuous rise in the annual global incidence rate of HCC, and it is estimated to reach >1 million cases by 2025. Emerging research in phytomedicine and chemotherapy has established the anti-cancer potential of phytochemicals, owing to their diverse biological activities. In this review, we report the major phytochemicals that have been explored in combating hepatocellular carcinoma and possess great potential to be used as an alternative or in conjunction with the existing HCC treatment modalities. An overview of the pre-clinical observations, mechanism of action and molecular targets of some of these phytochemicals is also incorporated.

The methanol extracts of roots, seeds, and leaves of Heracleum candolleanum (Wight et. Arn.) Gamble were subjected to in vitro anti-inflammatory and anticancer studies. The anti-inflammatory studies were carried out using HRBC membrane stabilization, inhibition of protein denaturation, and proteinase inhibitory methods. Cytotoxicity of the extracts was evaluated on cancer cells of various origins, namely, A431, A375, MDA-MB-231, U937, and HeLa, representing non-melanoma, melanoma, breast, acute myeloid leukemia, and cervical cancer cell lines respectively. From the present study it can be concluded that methanol extract of all the three parts of H. candolleanum may have significant anti-inflammatory activity against inflammatory based diseases or allied conditions. The study also revealed that the roots, leaves and seed extract possessed selective in vitro cytotoxicity, against five different human malignant cell lines.

The number of published studies on curcuminoids in cancer research, including its lead molecule curcumin and synthetic analogs, has been increasing substantially during the past two decades. Insights on the diversity of inhibitory effects they have produced on a multitude of pathways involved in carcinogenesis and tumor progression have been provided. As this wealth of data was obtained in settings of various experimental and clinical data, this review first aimed at presenting a chronology of discoveries and an update on their complex in vivo effects. Secondly, there are many interesting questions linked to their pleiotropic effects. One of them, a growing research topic, relates to their ability to modulate metabolic reprogramming. This review will also cover the use of curcuminoids as chemosensitizing molecules that can be combined with several anticancer drugs to reverse the phenomenon of multidrug resistance. Finally, current investigations in these three complementary research fields raise several important questions that will be put among the prospects for the future research related to the importance of these molecules in cancer research.

Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.

In triple-negative breast cancers, there exist tumor-specific vulnerabilities that can be targeted to avoid compensatory adaptation of cancer cells in response to standard pharmaceutical therapies. Natural moieties are well-known to possess a multitude of medicinal properties and deserve attention for TNBC prevention and therapy. To overcome drug resistance and efficacy issues, the exploration of natural moieties as targeting agents may emerge as dynamic, promising, and new therapeutic strategies to benefit TNBC patients. This chapter summarizes the role of polysaccharides, flavonoids, phenols, saponins, and taxanes in targeting TNBC. The potent role of herbal medicine in targeting molecular signalling pathways with special emphasis on their ability to target uncontrolled proliferation, metastasis, angiogenesis, and autophagy has also been discussed. Furthermore, the ability of herbal medicine in inhibiting PI3K/Akt/mTOR, STAT3, and Wnt/β-Catenin has also been explored. Combinational therapy comprising chemotherapeutic drugs and active plant constituents was also explored to overcome the complications of TNBC.