Heat stress in spermatogenesis: a redox-dependent decision network linking ROS, autophagy, and regulated cell death

Heat stress (HS) is an increasing threat to male reproductive health, disrupting spermatogenesis through complex and interdependent cellular responses within the seminiferous epithelium. Although excessive reactive oxygen species (ROS) production is a hallmark of HS, ROS also act as central regulators of cell fate decisions beyond their role in oxidative damage. Here, we propose a unified framework in which spermatogenic outcomes under HS are governed by a redox-dependent decision network, whereby ROS dynamics determine the balance between adaptive responses and regulated cell death (RCD). At moderate levels, ROS activate cytoprotective mechanisms, including antioxidant defences and autophagy, thereby promoting proteostasis and preserving cellular homeostasis. In contrast, excessive or sustained ROS accumulation induces lipid peroxidation, mitochondrial dysfunction, and impaired autophagic flux, driving the transition toward interconnected RCD pathways, including apoptosis, ferroptosis, and pyroptosis. Autophagy emerges as a central regulatory checkpoint in this network, acting as a molecular rheostat that modulates the shift between adaptation and cell death. Importantly, HS effects are stage-specific across spermatogenesis. Spermatogonia exhibit relative resilience due to efficient redox buffering and autophagic competence, whereas spermatocytes represent a critical vulnerability point, marked by heightened oxidative sensitivity and a strong propensity toward apoptosis. Post-meiotic germ cells are particularly susceptible to disruptions in structural remodelling and membrane integrity, while Sertoli cells act as key regulators of the redox microenvironment and amplifiers of HS-induced damage. Finally, we highlight redox balance modulation as a promising strategy to mitigate HS-induced reproductive damage. However, effective antioxidant interventions must be precisely calibrated to preserve physiological redox signalling and autophagic function rather than indiscriminately suppress ROS. Together, this framework provides a mechanistic basis for understanding how HS regulates germ cell fate and identifies potential targets for preserving male fertility under environmental and physiological thermal stress.