Probenecid and Eugenol Mitigate Testosterone Induced Benign Prostatic Hyperplasia by Targeting Uric Acid‐Induced Inflammation and Pro‐Survival Pathways

Background Benign prostatic hyperplasia (BPH) is a prevalent condition among aging males, significantly impacting their quality of life. Emerging evidence links elevated uric acid (UA) levels to prostatic inflammation and hyperplasia, potentially through oxidative stress and activation of proliferative pathways. However, the role of UA in BPH pathogenesis remains poorly defined. The study aims to investigate the potential protective effects of a natural phenolic compound, eugenol, and/or probenecid against testosterone‐BPH in rats, along with the possible underlying mechanisms. Methods BPH was induced by administering testosterone (3 mg/kg; s.c.) for 2 weeks, either alone or following a 1‐week pretreatment with probenecid (200 mg/kg/day; i.p.), eugenol (10 mg/kg/day; p.o.), or their combination. Results The results demonstrated a significant increase in prostate index, cell survival markers such as cyclin D1 expression, and histopathological features indicative of BPH following testosterone administration. Furthermore, testosterone led to elevated uric acid levels, oxidative stress, inflammatory markers, and activation of pro‐survival pathways including PI3‐K/Akt/mTOR and NFκB. However, treatment with probenecid, eugenol, or their combination effectively attenuated these alterations, demonstrating their anti‐inflammatory, antioxidative, and anti‐hyperproliferative effects. Notably, combination therapy exhibited superior efficacy compared to individual treatments. These findings suggest that probenecid and eugenol may mitigate testosterone‐induced BPH by targeting the uric acid‐induced inflammation and pro‐survival pathways. Conclusions This study provides novel insights into the therapeutic potential of probenecid and eugenol as adjunctive treatments for BPH, offering promising avenues for further clinical investigation.