Febuxostat alleviates testicular dysfunction induced by cyclophosphamide in rats via modulation of pyroptosis and mTOR autophagy axis.

Cyclophosphamide (CP) has long been employed in cancer treatment as well as in therapeutic regimens for autoimmune diseases. Despite its clinical value, one of its major drawbacks is testicular damage which may be due to disruption of antioxidant defenses, amplification of inflammatory responses, and suppression of autophagy. Febuxostat is a xanthine oxidase inhibitor with promising antioxidant, anti-inflammatory, and autophagy-inducing effects. The present study investigated whether febuxostat could mitigate CP-induced testicular toxicity in a rat model. Fifty male Sprague-Dawley rats were aligned into five groups: a control group, a CP-only group, and three CP-treated groups receiving febuxostat at doses of 5, 10, or 15 mg/kg/day. Seminal fluid, blood samples, and testicular tissues were collected and analyzed through biochemical assays and pathological examinations. Febuxostat dose-dependently restored the hormonal balance, enhanced antioxidant defenses, increased sirtuin-1 levels, and modulated both NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-driven pyroptosis and mammalian target of rapamycin (mTOR)-autophagy axis in the testicular tissues of CP-treated rats compared with CP-only rats. These improvements were consistently observed in the histopathological and immunohistochemical evaluations. Owing to its antioxidant, anti-inflammatory, autophagy-promoting, and pyroptosis-modulating effects, febuxostat may show promise as a potential therapeutic option for reducing CP-related gonadal dysfunction in males.