The gut–brain–cancer axis represents a novel and intricate connection between the gut microbiota, neurobiology, and cancer progression. Recent advances have accentuated the significant role of gut microbiota metabolites in modulating systemic processes that influence both brain health and tumorigenesis. This paper explores the emerging concept of metabolite-mediated modulation within the gut–brain–cancer connection, focusing on key metabolites such as short-chain fatty acids (SCFAs), tryptophan derivatives, secondary bile acids, and lipopolysaccharides (LPS). While the gut microbiota’s impact on immune regulation, neuroinflammation, and tumor development is well established, gaps remain in grasping how specific metabolites contribute to neuro–cancer interactions. We discuss novel metabolites with potential implications for neurobiology and cancer, such as indoles and polyamines, which have yet to be extensively studied. Furthermore, we review preclinical and clinical evidence linking gut dysbiosis, altered metabolite profiles, and brain tumors, showcasing limitations and research gaps, particularly in human longitudinal studies. Case studies investigating microbiota-based interventions, including dietary changes, fecal microbiota transplantation, and probiotics, demonstrate promise but also indicate hurdles in translating these findings to clinical cancer therapies. This paper concludes with a call for standardized multi-omics approaches and bi-directional research frameworks integrating microbiome, neuroscience, and oncology to develop personalized therapeutic strategies for neuro-cancer patients.

Early detection and accurate cancer diagnosis are crucial for improving patient outcomes and survival rates. This review presents a comprehensive and updated synthesis of emerging biomarkers, essential for providing non-invasive, efficient, and reliable methods to identify cancer in its early stages. An extensive literature review focuses on recent studies and advancements in both traditional and emerging biomarkers, including circulating tumor DNA (ctDNA), exosomes, liquid biopsies, microRNAs (miRNAs), and immunotherapy biomarkers, which show promising potential for early cancer detection. Liquid biopsies, nanobiosensors, artificial intelligence, and next-generation sequencing (NGS) are transforming biomarker discovery and application. Key challenges include low concentration and fragmentation, as well as clearance of ctDNA, the complexity of exosome isolation, inter-patient variability in miRNA expression, and the absence of clinical standardization. We also highlight the translational barriers in low-resource settings and suggest strategies for future implementation. We also underscore the limited diagnostic accessibility in low-resource settings, emphasizing the importance of equity in future applications. Future research should prioritize overcoming current challenges, promoting multidisciplinary collaboration, and creating standardized protocols to enhance the clinical utility of this approach.

Chronic inflammation plays a crucial role in cancer development, yet the mechanisms linking the microbiome to inflammation-related carcinogenesis remain unclear. Emerging evidence suggests that microbiome-derived metabolites influence inflammatory pathways, presenting both challenges and opportunities for therapy. However, a deeper understanding of how these metabolites regulate inflammation and contribute to cancer prevention is still needed. This review explores recent advances in microbiome-derived metabolites and their roles in inflammation-related carcinogenesis. It highlights key molecular mechanisms, emerging therapies, and unresolved challenges. Synthesizing current research, including clinical trials and experimental models, bridges the gap between microbiome science and cancer therapy. Microbial metabolites such as short-chain fatty acids (SCFAs), polyamines, indoles, and bile acids play vital roles in regulating inflammation and suppressing cancer. Many metabolites exhibit potent anti-inflammatory and immunomodulatory effects, demonstrating therapeutic potential. Case studies show promising results, but challenges such as metabolite stability, bioavailability, and individual variability remain. Understanding microbiome–metabolite interactions offers novel strategies for cancer prevention and treatment. This review identifies knowledge gaps and proposes future research directions to harness microbiome-derived metabolites for innovative cancer therapies. Addressing these issues may pave the way for microbiome-targeted cancer interventions.

Cancers are increasingly common and significantly impact patients' quality of life and longevity. The role of macrophages in tumorigenesis is critical, and natural compounds have long been recognized as valuable sources of bioactive agents for treating this condition. However, no systematic review has been performed on the role of phytochemicals impacting tumorigenesis by M1/M2 macrophage polarization. The aim of this study is to systematically review phytochemicals that relieve tumorigenesis by impacting M1/M2 macrophage polarization and investigate related signaling pathways. This systematic review adheres to PRISMA 2020 guidelines and statements. Scientific databases, MEDLINE, Scopus, and Web of Science, have been searched from inception to October 2023. This review includes English original articles on the role of phytochemicals, whole plant extracts, and polyherbal formulas in ameliorating tumorigenesis through M1/M2 polarization while excluding non-English articles, non-original research, and unrelated studies according to title, abstract, and full-text screening. Shreds of evidence were gathered from cellular and animal studies about the beneficial impacts of phytochemicals against tumorigenesis by impacting M1/M2 macrophage polarization. Critical assessment of in vitro and in vivo studies was performed by the CRIS and ARRIVE guidelines. Due to the high level of heterogeneity of the collected data, only a narrative synthesis was performed. Of 741 collected articles, only 35 remained. Polyphenols are the most highlighted group. Phytochemicals affect cytokines related to M1, such as CD80, CD86, CD64, and iNOS, and M2, like CXCR-1, CXCR-2, and TGF-β, in various cancer models. Together, these compounds exerted protective effects against tumorigenesis in preclinical cancer models. Furthermore, high-quality clinical experiments are recommended to cover the limitations of the current study, which are reliance on preclinical evidence, lack of clinical trials, and exclusion of non-English and grey literature.

Symplocamide A (Sym A), a 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclodepsipeptide derived from the marine cyanobacterium Symploca sp., has emerged as a promising candidate in anticancer research. With potent serine protease and proteasome inhibition, Sym A has demonstrated nanomolar cytotoxicity across several cancer cell lines, including lung and neuroblastoma models. This review critically assesses the anti-cancer mechanisms, pharmacokinetic properties, synthetic approaches, and translational limitations of Symplocamide A, highlighting its potential and challenges as a therapeutic agent in oncology. A systematic literature review was performed using PubMed, Scopus, Web of Science, Google Scholar, and the TRIP database, incorporating studies published until March 2025. Articles were selected based on predefined inclusion criteria focusing on Sym A’s anticancer activity, mechanisms of action, bioavailability, synthesis, and toxicity profiles. Sym A exhibits selective cytotoxicity toward various cancer cell lines, notably inhibiting chymotrypsin with over 200-fold greater potency than trypsin. Structural analysis underscores the role of Ahp and brominated tyrosine residues in target affinity and stability. Pharmacokinetic modeling indicates favorable intestinal absorption and drug-likeness, although brain penetration is limited. Synthetic production remains inefficient, with low overall yield. No in vivo or clinical studies have yet been reported. Toxicological concerns are heightened by its structural similarity to cyanotoxins, necessitating cautious evaluation. Symplocamide A demonstrates high preclinical anticancer potential through protease inhibition and favorable bioavailability traits. Nonetheless, its clinical translation is hindered by synthesis challenges, the absence of in vivo validation, and undefined toxicity. Further studies are warranted to evaluate its therapeutic window, optimize synthetic accessibility, and assess safety in vivo.

Cancer remains the second leading cause of death globally, driving the need for innovative therapies. Among natural compounds, maytansinoids have shown significant promise, contributing to nearly 25

Cancer represents a growing cause of death and a threat to public health worldwide; thus, there is an urgent need to understand its pathological mechanism and design effective therapies. The Hippo pathway regulates diverse cellular processes under physiological conditions; however, its dysregulation is associated with several types of cancer, including lung, pancreatic, colorectal, breast, and prostate cancer. Consequently, compounds targeting deregulated Hippo components represent potential treatments for a broad spectrum of cancers. Nonetheless, currently, there is limited information integrating the growing evidence of this potential. Therefore, the review's objective is to provide insight into the potential efficacy of targeting the Hippo/yes-associated protein (YAP) pathway for cancer therapy. First, we describe the molecular mechanisms of the Hippo signaling pathway in physiological conditions and several cancer types. We then provide an overview of natural products and synthetic compounds targeting this pathway, highlighting their potential applications in treating diverse cancers. We also discuss relevant preclinical and clinical studies of compounds targeting the Hippo pathway in cancer. Finally, we summarize our findings and offer recommendations for future research. This review emphasizes the role of the Hippo/YAP pathway in cancer and the potential of natural products and synthetic compounds targeting this pathway for cancer treatment.

Molecular crosstalk between the gut microbiome and human diet represent a potential therapeutic avenue requiring further investigation as it can be applied to human health management and treatment. Colon cancer, the third leading cause of cancer mortality, is often linked to the gut microbiome. In vitro and in vivo studies and metagenomic research have revealed alterations in gut microbial flora among diseased individuals. The human diet is connected to these changes in microbial inhabitants related to the pathophysiology underlying colorectal cancer (CRC). Polyphenols are well-studied, naturally occurring plant secondary metabolites recognized for their anti-inflammatory and antioxidant properties. The anticancer activities of these compounds are increasingly reported, offering insights into the administration of these natural molecules for managing various types of cancer and developing novel medications from them. Recent investigations have highlighted the prebiotic-like effects of these compounds on gut microbial dysbiosis and their metabolism concerning colorectal cancer, influencing colon cancer by interfering with multiple signaling pathways. This review will focus on the existing literature regarding the prebiotic potential of dietary polyphenols, and further research in this area would be valuable, as the integration of artificial intelligence (AI) and machine learning (ML) can enable analysis of the connections between unique gut microbiome profiles and other dependent factors such as physiological and genetic variables, paving the way for personalized treatment strategies in gut microbiome-based health management and precision medicine.

Background: The incidence of early-onset gastrointestinal cancer in individuals under 50 has been rising at an alarming rate in recent years. A major challenge in standard therapeutic interventions is the ability of cancer cells to evade apoptosis, which leads to chemoresistance and promotes cancer progression and metastasis. As a result, non-apoptotic forms of cell death, such as ferroptosis, have gained considerable attention as potential therapeutic interventions. Ferroptosis is a unique cell death characterized by iron-dependent lipid peroxidation and regulated through multiple signaling pathways. Cancer cells rely more on iron and are more sensitive to ferroptosis than normal cells. Recently, interest has surged in using natural compounds, particularly flavonoids, as anticancer agents. Flavonoids are increasingly recognized as potent inducers of ferroptosis, offering new therapeutic strategies in cancer therapy. Aim of the review: This review provides a detailed overview of current preclinical evidence on the therapeutic potential of flavonoids that induce ferroptosis in gastrointestinal cancers. First, the general mechanisms of ferroptosis are described, followed by an overview of synthetic compounds or small-molecule modulators. Then, flavonoids are introduced and described in terms of their classification, chemical structure, and anticancer activity. Finally, the gaps, challenges, and future scope of research are addressed. Key scientific concepts of review: Flavonoid modulators of ferroptosis target GPX4, the system Xc−, lipid metabolism, and iron metabolism pathways, in addition to various other pathways, to initiate the cell death process and inhibit carcinogenesis. We hypothesize that flavonoid-induced ferroptosis presents a strategic intervention in cancer therapy, serving as both anticancer agents and sensitizers to enhance the efficacy of current treatments.

Cancer drug resistance poses a significant challenge in oncology, primarily driven by cancer cell plasticity, which promotes tumor initiation, progression, metastasis, and therapeutic evasion in many different cancers. Breast cancers (BCs) are a prominent example of that, with an estimated 2.3 million new cases and 670,000 BC-related deaths registered worldwide annually. Triple-negative BC is especially challenging for treatments demonstrating particularly aggressive disease course, an early manifestation of metastatic disease, frequent drug-resistant cancer types, and poor individual outcomes. Although chemosensitizing agents have been developed, their clinical utility in oncology remains unproven. The mitogen-activated protein kinase (MAPK) pathway is considered a critical regulator of intracellular and extracellular signaling highly relevant for both — genetic and epigenetic modifications. Dysregulation of the MAPK signaling pathways plays a significant role in conferring chemoresistance in BC. Contextually, targeting the MAPK pathway represents a promising strategy for overcoming drug resistance and enhancing the therapeutic efficacy of anticancer agents in BC treatment. On the other hand, flavonoids, a prominent class of phytochemicals, are key modulators of MAPK signaling. Flavonoids interact with the ERK, JNK, p38, and ERK5 pathways of the MAPK signaling cascade and present a promising avenue for developing novel anti-cancer therapies and re-sensitizing agents for the treatment of BC. Compounds such as quercetin, kaempferol, genistein, luteolin, myricetin, EGCG, baicalein, baicalin, nobiletin, morin, delphinidin, acacetin, isorhamnetin, apigenin, silymarin, among others, have been identified as specific modulators of MAPK signaling, exerting complex downstream effects in BC cells increasing therewith drug efficacy and suppressing tumor growth and aggressivity. These properties reflect mechanisms of great clinical relevance to overcome therapeutic resistance in overall BC management. This article highlights corresponding mechanisms and provides clinically relevant illustrations in the framework of 3P medicine for primary (protection of individuals at high risk against health-to-disease transition) and secondary care (protection against metastatic BC progression). 3PM novelty makes good use of patient phenotyping and stratification, predictive multi-level diagnostics, and application of Artificial Intelligence (AI) tools to the individualized interpretation of big data — all proposed for cost-effective treatments tailored to individualized patient profiles with clear benefits to patients and advanced BC management.

The intricate relationship between anticancer drugs and the gut microbiome influences cancer treatment outcomes. This review paper focuses on the role of microbiome integrity in enhancing the efficacy and safety of anticancer drug therapy, emphasizing the pharmacokinetic interactions between anticancer drugs and the gut microbiota. It explores how disruptions to microbiome composition, or dysbiosis, can alter drug metabolism, immune responses, and treatment side effects. By examining the mechanisms of microbiome disruption caused by anticancer drugs, this paper highlights specific case studies of drugs like cyclophosphamide, 5-fluorouracil, and irinotecan, and their impact on microbial diversity and clinical outcomes. The review also discusses microbiome-targeted strategies, including prebiotics, probiotics, postbiotics, and fecal microbiota transplantation (FMT), as promising interventions to enhance cancer treatment. Furthermore, the potential of microbiome profiling in personalizing therapy and integrating these interventions into clinical practice is explored. Finally, this paper proposes future research directions, including developing novel biomarkers and a deeper comprehension of drug–microbiome interactions, to respond to current gaps in knowledge and improve patient outcomes in cancer care.

Early-onset colorectal cancer (EOCRC) is emerging as a significant global health concern, particularly among individuals under the age of 50. This alarming trend has coincided with an increase in the consumption of processed foods that often rely heavily on synthetic preservatives. At the same time, these additives play a critical role in ensuring food safety and shelf life. Growing evidence suggests that they may contribute to adverse gut health outcomes, which is a known risk factor in colorectal cancer development. At the same time, synthetic preservatives serve essential roles such as preventing microbial spoilage, maintaining color, and prolonging shelf life. Natural preservatives, on the other hand, not only provide antimicrobial protection but also exhibit antioxidant and anti-inflammatory properties. These contrasting functions form the basis of current discussions on their safety and health implications. Despite their widespread use, the long-term health implications of synthetic preservatives remain inadequately understood. This review synthesizes recent clinical, epidemiological, mechanistic, and toxicological data to examine the potential link between synthetic food preservatives and EOCRC. Particular focus is placed on compounds that have been associated with DNA damage, gut microbiota disruption, oxidative stress, and chronic inflammation, which are the mechanisms that collectively increase cancer risk. In contrast, natural preservatives derived from plants and microbes are gaining attention for their antioxidant, antimicrobial, and possible anti-inflammatory effects. While these alternatives show promise, scientific validation and regulatory approval remain limited. This review highlights the urgent need for more rigorous, long-term human studies and advocates for enhanced regulatory oversight. It advocates for a multidisciplinary approach to developing safer preservation strategies and highlights the importance of public education in making informed dietary choices. Natural preservatives, though still under investigation, may offer a safer path forward in mitigating EOCRC risk and shaping future food and health policies.

Early-life exposure to lifestyle-associated metabolic alterations could be a key contributor to early-onset colorectal cancer (EOCRC). Notably, insulin resistance (InsR)-linked hyperinsulinemia, elevated levels of insulin-like growth factors, and chronic inflammation could trigger EOCRC by modulating gene expression/pathways that support carcinogenesis/anti-apoptosis. Here, we discuss how InsR could be the trigger that offsets metabolic homeostasis in young individuals, leading to EOCRC. Furthermore, we emphasize the need for lifestyle interventions, early detection, and targeted therapeutic interventions to mitigate this growing health concern.

Incretins, such as Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP), are hormones known to stimulate insulin secretion and are widely used in the management of type 2 diabetes mellitus (T2DM). Recent evidence suggests that these hormones, and incretin-based therapies like DPP-4 inhibitors and GLP-1 receptor agonists, may have proliferative effects on pancreatic β-cells, raising concerns about a potential link to certain cancers. This review aims to evaluate both the beneficial and detrimental effects of incretins in cancer development and therapy. We conducted a comprehensive review of clinical cohort studies, as well as in vivo and in vitro investigations, to assess the dual role of incretin-based therapies in cancer risk and potential treatment. The molecular and cellular mechanisms underlying these effects were critically analyzed. While some studies have suggested an increased risk of pancreatic, thyroid, cholangiocarcinoma, and colorectal cancers associated with incretin therapies—especially in genetically predisposed individuals—other research has demonstrated anticancer effects in prostate, breast, ovarian, and other cancers through various mechanisms. These include inhibition of tumor proliferation, induction of apoptosis, and modulation of immune responses. Although incretin-based drugs may pose a cancer risk in specific tissues, particularly in susceptible individuals, their therapeutic potential in mitigating other cancer types appears promising. The overall evidence suggests that the benefits of incretins may outweigh the risks when patient-specific factors are carefully considered.

Background Studies on the interaction of cancer cells with other cells (fibroblasts, endothelial cells, and immune cells) of the tumor microenvironment (TME) have led to the development of many novel targeted therapies. More recently, the notion that neuronal cells of the TME could impact various processes supporting cancer progression has gained momentum. Tumor-associated neurons release neurotransmitters into the TME that, in turn, bind to specific receptors on different target cells, supporting cancer progression. Furthermore, cancer cells secrete nerve growth factors and neurotropic factors that facilitate the growth of nerve fibers that innervate the tumor. In this regard, the beta 2-adrenergic receptors (β2-AR), which respond to neurotropic factors such as catecholamines, are highly expressed in cancer cells, including colorectal cancer (CRC). Aim of Review Understanding the complexity of the neuronal-cancer axis and identifying targets for molecular therapy is essential. This review focuses on the role of β2-AR in neuro-neoplastic cell signaling during CRC progression and its clinical relevance to diagnosis, prognosis, and treatment. Key Scientific Concepts of Review The expression of β2-AR on CRC and various other cells of the colorectal TME, along with its responsiveness to agonists or antagonists, is of particular interest since targeting β2-AR and related pathways could curb CRC growth. In the current article, we provide an in-depth review of the possible central role of β2-AR in CRC cancer progression, with special reference to stress-induced activation of the nervous system, catecholamine release, hyperactivation of adrenergic signaling concerning the activation of downstream oncogenic pathways, immuno-modulation, and metastasis. The article also emphasizes the clinical significance of β2-AR expression, its potential as a diagnostic/prognostic biomarker, and the benefits of targeting (by repurposing β-blockers) β2-AR in combination therapies to improve the therapeutic efficacy of current treatment options and overall patient outcomes.

Foodborne pathogens are microorganisms that cause illness through contamination, presenting significant risks to public health and food safety. This review explores the metabolites produced by these pathogens, including toxins and secondary metabolites, and their implications for human health, particularly concerning cancer risk. We examine various pathogens such as Salmonella sp., Campylobacter sp., Escherichia coli, and Listeria monocytogenes, detailing the specific metabolites of concern and their carcinogenic mechanisms. This study discusses analytical techniques for detecting these metabolites, such as chromatography, spectrometry, and immunoassays, along with the challenges associated with their detection. This study covers effective control strategies, including food processing techniques, sanitation practices, regulatory measures, and emerging technologies in pathogen control. This manuscript considers the broader public health implications of pathogen metabolites, highlighting the importance of robust health policies, public awareness, and education. This review identifies research gaps and innovative approaches, recommending advancements in detection methods, preventive strategies, and policy improvements to better manage the risks associated with foodborne pathogens and their metabolites.

Cancer remains one of the leading causes of death in the world. Despite the considerable success of conventional treatment strategies, the incidence and mortality rates are still high, making developing new effective anticancer therapies an urgent priority. Ginsenoside Rg5 (Rg5) is a minor ginsenoside constituent obtained exclusively from ginseng species and is known for its broad spectrum of pharmacological activities. This article aimed to comprehensively review the anticancer properties of Rg5, focusing on action mechanisms, structure–activity relationship (SAR), and pharmacokinetics attributes. The in vitro and in vivo activities of Rg5 have been proven against several cancer types, such as breast, liver, lung, bone, and gastrointestinal (GI) cancers. The modulation of multiple signaling pathways critical for cancer growth and survival mediates these activities. Nevertheless, human clinical studies of Rg5 have not been addressed before, and there is still considerable ambiguity regarding its pharmacokinetics properties. In addition, a significant shortage in the structure–activity relationship (SAR) of Rg5 has been identified. Therefore, future efforts should focus on further optimization by performing extensive SAR studies to uncover the structural features essential for the potent anticancer activity of Rg5. Thus, this review highlights the value of Rg5 as a potential anticancer drug candidate and identifies the research areas requiring more investigation.

Melatonin, an endogenous neurohormone produced by the pineal gland, has received increased interest due to its potential anti-cancer properties. Apart from its well-known role in the sleep–wake cycle, extensive scientific evidence has shown its role in various physiological and pathological processes, such as inflammation. Additionally, melatonin has demonstrated promising potential as an anti-cancer agent as its function includes inhibition of tumorigenesis, induction of apoptosis, and regulation of anti-tumor immune response. Although a precise pathophysiological mechanism is yet to be established, several pathways related to the regulation of cell cycle progression, DNA repair mechanisms, and antioxidant activity have been implicated in the anti-neoplastic potential of melatonin. In the current manuscript, we focus on the potential anti-cancer properties of melatonin and its use in treating and managing pediatric osteosarcoma. This aggressive bone tumor primarily affects children and adolescents and is treated mainly by surgical and radio-oncological interventions, which has improved survival rates among affected individuals. Significant disadvantages to these interventions include disease recurrence, therapy-related toxicity, and severe/debilitating side effects that the patients have to endure, significantly affecting their quality of life. Melatonin has therapeutic effects when used for treating osteosarcoma, attributed to its ability to halt cancer cell proliferation and trigger apoptotic cell death, thereby enhancing chemotherapeutic efficacy. Furthermore, the antioxidative function of melatonin alleviates harmful side effects of chemotherapy-induced oxidative damage, aiding in decreasing therapeutic toxicities. The review concisely explains the many mechanisms by which melatonin targets osteosarcoma, as evidenced by significant results from several in vitro and animal models. Nevertheless, if further explored, human trials remain a challenge that could shed light and support its utility as an adjunctive therapeutic modality for treating osteosarcoma.

Cancer is a collection of illnesses characterized by aberrant cellular proliferation that can infiltrate or metastasize to distant anatomical sites, posing a notable threat to human well-being due to its substantial morbidity and death rates worldwide. The potential of plant-derived natural compounds as anticancer medicines has been assessed owing to their favorable attributes of few side effects and significant antitumor activity. Mangrove plants and their derived compounds have been scientifically shown to exhibit many significant beneficial biological activities, such as anti-inflammatory, immunomodulatory, antioxidant, neuroprotective, cardioprotective, and hepatoprotective properties. This study summarized mangrove plants and their derived compounds as potential anticancer agents, with an emphasis on the underlying molecular mechanisms. To explore this, we gathered data on the preclinical (in vivo and in vitro) anticancer effects of mangrove plants and their derived compounds from reputable literature spanning 2000 to 2023. We conducted thorough searches in various academic databases, including PubMed, ScienceDirect, Wiley Online, SpringerLink, Google Scholar, Scopus, and the Web of Science. The results demonstrated that mangrove plants and their derived compounds have promising anticancer properties in preclinical pharmacological test systems through various molecular mechanisms, including induction of oxidative stress and mitochondrial dysfunction, cytotoxicity, genotoxicity, cell cycle arrest, apoptosis, autophagy, antiproliferative, antimetastatic, and other miscellaneous actions. Upon thorough observation of the pertinent information, it is suggested that mangrove plants and their derived chemicals may serve as a potential lead in the development of novel drugs for cancer therapy. The primary goal of the present study was to evaluate the anticancer abilities of mangrove plants and their compounds in great detail. In addition, we seek to investigate the molecular processes that give rise to mangrove plants and their phytochemical anticancer properties, focusing on their possible application in cancer treatment, which could provide valuable insights for future investigations and the development of novel therapeutic approaches.image

Cancer remains a global health challenge, with drug resistance and disease recurrence posing significant obstacles despite advances in immunotherapy and targeted treatments. This has driven interest in natural products as sources of novel anticancer agents. Withania somnifera (Ashwagandha), a well-regarded plant in Ayurvedic medicine, is noted for its various therapeutic properties, including anticancer effects. Among its bioactive compounds, Withaferin A (WFA), a steroidal lactone, has shown notable promise in reducing inflammation, angiogenesis, and tumor proliferation with minimal toxicity. This review examines the anticancer properties of WFA, with a focus on its mechanisms of action, therapeutic efficacy, and safety profile across various cancer types. A comprehensive literature review was conducted, compiling data from in vitro and in vivo studies that investigate WFA’s impact on cancer hallmarks, including apoptosis induction, angiogenesis reduction, and metastasis inhibition. Key molecular interactions with NFκB, STAT, HSP90, estrogen receptors, p53, and TGFβ pathways are highlighted. Findings indicate that WFA exhibits significant anticancer activity by modulating critical signaling pathways and inducing apoptosis with minimal adverse effects. In preclinical models, WFA demonstrated therapeutic potential across multiple cancers, such as breast, colon, prostate, ovarian, lung, and brain cancers. WFA represents a promising candidate for future cancer therapies, particularly as a natural adjuvant that could enhance treatment efficacy with low toxicity. Further clinical trials are needed to explore WFA’s full potential and confirm its safety in human oncology.