Casticin Inhibits AKR1C3 and Enhances Abiraterone Efficacy in Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) remains a major therapeutic challenge due to the development of resistance to androgen deprivation and next-generation antiandrogens such as abiraterone (ABI). One of the key mechanisms underlying this resistance involves overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme contributing to intratumoral androgen biosynthesis. In this study, casticin (CAS), a flavonoid derived from Vitex agnus-castus , was identified as a potent inhibitor of AKR1C3. CAS demonstrated inhibitory activity in enzymatic assays (IC₅₀ = 5.99 µM), effectively reduced AKR1C3-dependent coumberone metabolism in 22Rv1 prostate cancer cells, and exhibited cytotoxicity preferentially in AKR1C3-expressing 22Rv1 cells compared to AKR1C3-low LNCaP cells. Importantly, CAS enhanced the antitumor efficacy of ABI in 22Rv1 cells, showing a synergistic effect (Combination Index 0.31–0.71), while no synergy was observed in LNCaP cells or in combination with enzalutamide. Molecular docking and dynamics simulations revealed stable binding of CAS in the AKR1C3 active site, with key hydrogen bonding and aromatic interactions supporting its inhibitory mechanism. These findings position CAS as a promising chemosensitizing agent that targets AKR1C3 to overcome ABI resistance in CRPC.