Timosaponin A3 Ameliorates Prostate Cancer Progression via Upregulating STARD4 Mediated Cholesterol Metabolism

ABSTRACT Prostate cancer (PCa) is a common and aggressive malignancy in men, often diagnosed at advanced stages with a poor five‐year survival rate. Despite therapeutic advances, effective treatments for castration‐resistant PCa remain lacking. Timosaponin A3 (TA3), a natural steroidal saponin derived from Anemarrhena asphodeloides Bunge, has shown potential anti‐tumor properties, but its role in PCa and the underlying mechanisms have not been fully elucidated. In this study, we demonstrate that TA3 significantly inhibits the proliferation, migration, and invasion of PCa cells in vitro , and suppresses tumor growth in xenograft models. Transcriptomic analysis revealed that TA3 exerts its anti‐tumor effects by modulating cholesterol metabolism. Elevated cholesterol levels were observed in PCa patients, and exogenous cholesterol administration reduced tumor growth in vivo . Notably, TA3 treatment upregulated the lipid transporter StAR related lipid transfer domain containing 4 (STARD4), a key regulator of cholesterol transport, which was confirmed to mediate the inhibitory effects of TA3 on PCa progression. Overexpression of STARD4 attenuated PCa development both in vitro and in vivo , while STARD4 knockdown abolished these effects. Collectively, our findings suggest that TA3 suppresses PCa progression by enhancing cholesterol metabolism via STARD4 upregulation, supporting its potential as a novel therapeutic agent for prostate cancer.