Oxidative Stress‐Related Programmed Cell Death in Male Infertility: Focussing on Ferroptosis

Oxidative stress is a common occurrence in testicular cells of infertile men and is considered a significant cause of male reproductive dysfunction. The increase in reactive oxygen species (ROS) leads to impaired spermatogenesis by activating caspases and generating free radicals from mitochondria, resulting in DNA damage and cell death through apoptosis. Additionally, oxidative stress in the testis triggers autophagy as an alternative form of programmed cell death in male germ cells. There is a complex interplay between autophagy and apoptosis in response to oxidative stress in male germ cells. Recent studies have shown that oxidative stress can also induce a form of cell death called ferroptosis, which is an iron-regulated, caspase-independent pathway. Ferroptosis is initiated by the inactivation of the antioxidant enzyme glutathione peroxidase 4 (GPX4) and the dysfunction of system Xc-, leading to iron-dependent lipid peroxidation. Therefore, a combination of apoptosis, autophagy and ferroptosis determines the fate of testicular cells under oxidative stress conditions. This review explored these three types of programmed cell death associated with oxidative stress in testicular cells and their implications for male infertility, with a focus on ferroptosis.