Therapeutic potential of Withaferin A in cancer-induced muscle and cardiac wasting.

Abstract

Cancer-induced cachexia is a multifactorial syndrome characterized by severe skeletal muscle and cardiac atrophy, contributing significantly to patient morbidity and mortality. Among its cardiac manifestations, right ventricular (RV) dysfunction remains an underrecognized yet critical predictor of poor prognosis across diverse malignancies. Despite its clinical significance, no FDA-approved therapies currently exist to address either cancer-associated cachexia or RV dysfunction, highlighting a major unmet medical need. Our recent studies investigated Withaferin A (WFA), a steroidal lactone derived from the Withania somnifera plant, as a potential therapeutic agent to mitigate these conditions. In preclinical studies of ovarian cancer-induced cachexia, WFA not only enhanced grip strength and improved skeletal muscle morphology but also restored LV function, as evidenced by multiple echocardiographic parameters. Mechanistically, WFA attenuated key cachexia-associated pathways, including NF-κB signaling, NLRP3 inflammasome activation, and fibrotic remodeling, while promoting proteostasis and mitochondrial homeostasis. This review integrates existing literature with new insights from our translational studies to underscore WFA's potential as a dual-action therapeutic targeting both muscular and cardiac aspects of cachexia. We further examine the pathophysiological basis of cancer-associated cachexia, the utility of murine models in elucidating cardiac cachexia mechanisms, and the challenges and future opportunities for clinical translation. Collectively, we aim to present a compelling rationale for advancing WFA as a "First-in-Class" therapy with the potential to change the treatment paradigm for cachexia in the oncology space.