The dual role of autophagy in Sertoli cells: mechanistic insights and research progress

Sertoli cells play a central role in maintaining testicular homeostasis and male fertility. Given their high metabolic activity and exposure to diverse stressors, the integrity and function of Sertoli cells are particularly vulnerable to intracellular quality control mechanisms. Autophagy, a conserved cellular degradation and recycling mechanism, plays a critical role in preserving Sertoli cell structure and function. Emerging evidence indicates that autophagy exerts a dual influence on Sertoli cell physiology: it is protective when moderately activated but becomes detrimental when excessively stimulated or impaired. This review summarizes recent advances in understanding how autophagy regulates Sertoli cell functions, including blood-testis barrier (BTB) dynamics, secretory activity, and energy metabolism. We highlight how oxidative stress, toxicant exposure, hormonal signaling, and autophagy-related genes modulate autophagic responses in Sertoli cells. Dysregulated autophagy has been associated with barrier disruption, aberrant cytokine secretion, and metabolic imbalance. These findings highlight autophagy as an important regulator that can function as both a guardian and a potential disruptor of testicular function. Understanding the mechanistic basis and regulatory thresholds of autophagy in Sertoli cells not only provides insight into testicular homeostasis but also lays the foundation for developing targeted intervention strategies aimed at key autophagy nodes to protect male fertility from environmental toxicants, metabolic stress, and aging-related challenges.