Regulated Cell Death in Reproductive Biology: Mechanisms and Therapeutic Opportunities

Abstract

Regulated cell death (RCD) has emerged as a fundamental determinant of cellular homeostasis and tissue remodeling, extending far beyond the classical concept of apoptosis. The identification of emerging RCD pathways, including ferroptosis, pyroptosis, necroptosis, cuproptosis, PANoptosis, and autophagy-dependent cell death, has expanded our understanding of reproductive physiology and disease. RCD mechanisms contribute to reproductive homeostasis and have been increasingly implicated in gametogenesis, folliculogenesis, embryonic development, implantation, placentation, and reproductive aging, while their dysregulation has been associated with infertility, recurrent implantation failure, recurrent pregnancy loss, pregnancy complications, endometriosis, polycystic ovary syndrome (PCOS), gynecological malignancies, and male reproductive disorders. This review provides a comprehensive overview of the molecular mechanisms governing RCD across reproductive physiology and disease, emphasizing the complex interplay between oxidative stress (OS), mitochondrial dysfunction, inflammation, immune regulation, metabolic reprogramming, and genetic and epigenetic networks. Particular attention is given to the contribution of emerging cell death pathways to reproductive disorders and their interactions with environmental and lifestyle factors, including endocrine-disrupting chemicals. In addition, current evidence regarding RCD-associated biomarkers, multi-omics approaches, and therapeutic strategies targeting specific cell death pathways is critically evaluated, with particular emphasis on distinguishing associative molecular signatures from functional evidence of RCD execution. By integrating recent advances from basic, translational, and clinical research, this review highlights the context-dependent role of RCD in reproductive biology and disease and identifies current limitations and future opportunities for RCD-informed diagnostics, patient stratification, and targeted therapeutic interventions in reproductive medicine.