HMGB1/NF-κB Axis, IL-8, and Cuproptosis Contribute to Cisplatin-Induced Testicular Injury: Protective Potential Effect of Thymol.

BACKGROUND: Cisplatin (CP) use is associated with testicular toxicity. Cuproptosis-related genes are associated with dysfunctional spermatogenesis. Additionally, the HMGB1/NF-κB axis has been involved in cuproptosis-mediated inflammation. The aim of the current study was to investigate the effect of CP toxicity on the HMGB1/NF-κB axis and cuproptosis in the rat testis. The effect of thymol was also explored. METHODS: Four groups of male Wistar rats were used: control, thymol (60 mg/kg P.O. daily for 2 weeks), CP (8 mg/kg i.p single injection), and CP+thymol. RESULTS: CP induced a significant decrease in serum testosterone and LH. CP-induced oxidative stress was evident by the modulation of oxidative stress markers. The expressions of IL-8, NF-κB, and HMGB1 were induced by CP treatment, accompanied by increased expression of cuproptosis genes, including SLC31A1, FDX1, and DLAT. On the other hand, thymol antagonized CP testicular injury. Thymol's effect was associated with reduced expressions of IL-8, NF-κB, HMGB1, and cuproptosis markers. CONCLUSIONS: Collectively, this study provides evidence of the possible potential role of the HMGB1/NF-κB axis and cuproptosis in CP-induced testicular injury and illustrates the protective effects of thymol against testicular damage, which are attributed, at least in part, to blunting HMGB1 and cuproptosis-related genes expression.