Is ferroptosis a cause for concern in male infertility?

Abstract

Ferroptosis, a recently identified form of regulated cell death, has emerged as a key player in the pathophysiology of various disorders, including male reproductive dysfunction. This review explores the interplay of ferroptosis with male reproductive health, focusing on the molecular mechanisms involved. Global male reproductive health has been deteriorating due to a combination of genetic, environmental, and lifestyle factors, including oxidative stress, reactive oxygen species (ROS), epigenetic alterations, and posttranslational modifications (PTMs). Ferroptosis is characterized by iron overload and lipid peroxidation, leading to testicular damage and impaired spermatogenesis, thus contributing to male infertility. While iron plays an essential role in maintaining spermatogenesis and testosterone production, its overload induces oxidative stress, ROS accumulation, and testicular ferroptosis, which disrupts normal reproductive function. Factors such as failure of antioxidant defense systems, exposure to xenobiotics (e.g., arsenite, cadmium, phthalates, bisphenol A, PM2.5), and alterations in ferroptosis-related genes (FRGs) further exacerbate testicular dysfunction. This review examines the critical role of lipid, iron, and glutathione metabolic pathways in ferroptosis induction, the effects of environmental xenobiotics on testicular health, and the potential therapeutic benefits of ferroptosis inhibitors in treating male infertility.