Ferroptosis in health and disease

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death that is driven by lipid peroxidation. In the past decade, it has emerged as a core pathogenic mechanism in a wide range of human diseases, such as neurodegenerative disorders, cardiovascular disease, cancer, and notably, reproductive dysfunction. This review provides a comprehensive overview of the molecular mechanisms underlying ferroptosis with a specific focus on the System Xc⁻-GSH-GPX4 axis, iron metabolism, lipid peroxidation, and the regulatory roles of key modulators such as Nrf2, ACSL4, and CISD2. This review also explores the physiological roles of ferroptosis in development, tissue homeostasis, and immune regulation, as well as its pathological contributions to obesity, diabetes mellitus, atherosclerosis, neurodegeneration, stroke, cancer, infectious diseases, and reproductive disorders. A substantial part of this review discusses the role of ferroptosis in the pathogenesis of reproductive disorders, such as male reproductive pathologies, including varicocele, testicular ischemia-reperfusion, cryptorchidism, oligospermia, erectile dysfunction, and testicular cancer, and female pathologies like primary ovarian insufficiency, polycystic ovary syndrome, endometriosis, ovarian cancer, and pre-eclampsia. Moreover, the interplay between ferroptosis and immune dysfunction in reproductive tract infections was highlighted. Furthermore, we evaluated current biomarkers, emerging therapeutic strategies, and key translational challenges, highlighting the promise of ferroptosis-modulating agents for novel diagnostic and therapeutic interventions in reproductive medicine and beyond.