Withaferin A: Mechanisms of action, therapeutic efficacy, and clinical potential in gastrointestinal cancer treatment: a comprehensive review

Withaferin A (WA), a bioactive compound isolated from Withania somnifera , has gained attention as a potent anticancer agent targeting multiple molecular pathways, including NF-κB, STAT3, PI3K/Akt, and p53 signaling. Its broad cytotoxic efficacy across diverse cancer models highlights its therapeutic promise; however, translation to clinical settings remains constrained by poor water solubility, rapid first-pass metabolism, and limited oral bioavailability. Recent advances in nanotechnology, such as polymeric nanoparticles, PEG-PLGA carriers, gold conjugates, and nanosponges, have substantially enhanced WA’s solubility, stability, and tumor-specific accumulation, offering new prospects for improved systemic delivery. Preclinical evidence discussed in this review indicates that WA exhibits significant anticancer activity against major gastrointestinal malignancies, including esophageal, gastric, colorectal, pancreatic, and liver cancers, primarily through modulation of apoptosis, oxidative stress, cell-cycle arrest, and oncogenic signaling pathways. Nonetheless, emerging clinical and case-report evidence of transient hepatotoxicity highlights the need for rigorous safety evaluation. A balanced translational strategy integrating formulation optimization, pharmacokinetic modeling, and comprehensive toxicological assessment is essential to define a safe therapeutic view. This review provides a comprehensive analysis of WA’s molecular mechanisms, therapeutic relevance, and recent advances in drug-delivery approaches, with particular emphasis on nanotechnology-based approaches aimed at overcoming its pharmacokinetic limitations and enhancing its potential application in gastrointestinal cancer treatment.