Food-derived androgen receptor (AR) antagonists present a promising avenue for the prevention of early prostate cancer and dietary interventions. This study investigates the impact of capsaicin, the principal bioactive dietary compound in chili peppers recognized for its anticancer effects, on AR-targeted mechanisms in early prostate cancer via both in vivo and in vitro approaches. In our findings, capsaicin significantly inhibited cell proliferation in the AR-positive prostate cancer cell line LNCaP, leading to a G0/G1 phase cell cycle arrest, with a reduction in proliferation rate by approximately 42 % at 0.08 mol/m3 after 72 h. The biological data derived from fluorescence polarization assay and cellular LNCaP models confirmed that capsaicin effectively diminished the transcriptional activity of AR by engaging its ligand-binding domain. Mechanistically, our results revealed that capsaicin enhanced the polyubiquitination of AR by fostering the interaction between MDM2, SKP2, and AR, leading to a notable reduction in AR protein levels by 60 % at 0.08 mol/m3 after 24 h. Additionally, in a xenograft model, high-dose capsaicin administration resulted in a 55 % decrease in tumor volume compared to the control group after 25 days, accompanied by a significant reduction in AR expression within tumor tissues. These results underscore capsaicin's potential as a dietary AR antagonist, which may play a crucial role in the prevention and treatment of prostate cancer.
