TRPV1 Downregulation Impairs Prostate Cancer Growth: Functional and Translational Insights from Cellular and <i>In Vivo</i> Models

The transient receptor potential vanilloid 1 (TRPV1), the canonical capsaicin (CAP) receptor, has been implicated across diverse pathologies, yet its role in prostate cancer (PCa) remains elusive. Here, we uncover TRPV1 as a key regulator of PCa progression and a mediator of CAP's antiproliferative effects. Through a comprehensive strategy combining proteomic profiling, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse modeling, and validation in human prostate biopsies, we assessed TRPV1 expression, its functional role, and its association with tumor markers. Both proteomic analysis and Western blotting of TRPV1-silenced cells revealed reduced expression of PCNA, Cyclin B1, and AURKA, along with elevated levels of the cell cycle inhibitor p21. Similarly, CAP treatment resulted in comparable changes in the proteomic profile. Functional assays demonstrated that both TRPV1 knockdown and CAP exposure significantly impaired cell cycle progression and mitosis. Moreover, sustained CAP treatment led to a reduction in TRPV1 expression, further supporting its oncogenic role. In TRAMP mice, a high-fat diet feeding elevated plasma PSA levels and TRPV1 expression in the prostate, whereas CAP supplementation reversed these effects. Importantly, TRPV1 expression correlated positively with cancer stem cell markers in both murine models and human samples. Collectively, our results reveal that TRPV1 is not only overexpressed in PCa but also contributes to proliferation regulation and stemness features, positioning it as a potential diagnostic and prognostic biomarker for prostate cancer.