Sertraline significantly reduced cell viability in PC3 and DU‐145 prostate cancer cells (IC50≈9–24 μM)Inhibited cell migrationReduced colony formation (anchorage‐independent growth)Induced apoptosis (Annexin V/PI assay)Caused G0/G1 cell cycle arrest.Downregulated Bcl‐2 and VEGF (pro‐survival and angiogenesis genes)Upregulated caspase‐8 and DR5 (extrinsic apoptosis pathway)Showed synergistic/additive effects with cisplatin, 5‐FU, and raloxifene in both cell lines. Here, ANXA5 is linked to prostate cancer.