Targeting programmed cell death in male infertility: pathogenic mechanisms and therapeutic strategies.

Male infertility arises from diverse pathological processes, among which dysregulated cell death is a key contributor. Increasing evidence indicates that programmed cell death (PCD) plays a critical role in male infertility and involves multiple regulated forms, including apoptosis, autophagy, pyroptosis, and ferroptosis, as well as the clearance of dying cells through efferocytosis. Unlike necrosis, PCD is an actively regulated process controlled by gene expression and is essential for maintaining testicular homeostasis by eliminating damaged or superfluous cells and modulating cellular defense responses in germ cells, Sertoli cells, and Leydig cells. Aberrant activation or insufficient regulation of these pathways, often driven by oxidative stress, inflammation, or metabolic imbalance, can disrupt spermatogenesis and impair the testicular microenvironment. Therefore, understanding PCD is crucial for clarifying the mechanisms underlying male infertility and for guiding therapeutic development. This review summarizes recent advances in five PCD pathways in male infertility: apoptosis, autophagy, pyroptosis, ferroptosis, and efferocytosis. It focuses on shared molecular nodes, pathway crosstalk, and potential therapeutic targets.