The Role of the p62‐Keap1‐Nrf2 Pathway in Protecting Sertoli Cells Against Mono‐(2‐ethylhexyl)phthalate‐induced Ferroptosis

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer linked to testicular toxicity. Mono-(2-ethylhexyl) phthalate (MEHP) is the main bioactive metabolite of DEHP. The aim of this study was to investigate the protective role of the p62-Keap1-Nrf2 pathway against ferroptosis in Sertoli cells, which are crucial for normal testicular function, utilizing a cell model of MEHP-induced damage. Sertoli cells were treated with MEHP in vitro to assess the effects of MEHP on cell viability, the occurrence of ferroptosis, and the activation status of the p62-Keap1-Nrf2 pathway. Exposure to MEHP resulted in elevated levels of lipid peroxidation and indicators of iron accumulation in Sertoli cells, indicating oxidative stress and cell death associated with iron overload. Following p62 and Nrf2 gene knockdown in Sertoli cells, MEHP-induced ferroptosis was exacerbated. The p62-Keap1-Nrf2 signaling pathway played a critical role in protecting Sertoli cells from MEHP-induced ferroptosis, potentially mitigating testicular injury in mice. These findings elucidate the molecular mechanisms underlying MEHP toxicity and reveal potential therapeutic strategies for preventing testicular dysfunction associated with MEHP exposure.