Therapeutic Potential of Withaferin A from Withania somnifera in Cancer: A Comprehensive Phytotherapeutic Review

Abstract

Withaferin A, a steroidal lactone and major withanolide of Withania somnifera (Ashwagandha), has gained considerable attention for its potent anticancer potential. Abundantly present in the leaves and roots, WA exhibits a broad pharmacological profile encompassing anti-inflammatory, immunomodulatory, antioxidant, and cytotoxic properties. Extensive preclinical studies reveal that WA exerts anticancer effects through multiple, interrelated mechanisms. These include apoptosis induction via activation of p53, Bax, and caspases while inhibiting Bcl-2; cell cycle arrest at the G2/M phase through downregulation of cyclins and cyclin-dependent kinases; oxidative stress modulation by enhancing reactive oxygen species generation and impairing antioxidant defenses; oncogenic signaling suppression involving inhibition of NF-κB, STAT3, Akt, and Notch pathways; and anti-metastatic/anti-angiogenic activity through downregulation of matrix etalloproteinase-9 and vascular endothelial growth factor. Notably, WA demonstrates selective cytotoxicity toward cancer cells while sparing normal tissues, making it an attractive candidate for cancer chemoprevention and therapy. However, clinical translation remains limited due to bioavailability challenges, warranting advanced formulation strategies and well-designed clinical trials. This review provides a comprehensive analysis of WA’s phytochemistry, molecular mechanisms, and therapeutic relevance, underscoring its potential as a multi-targeted phytotherapeutic agent in oncology.