Autophagy in testicular physiology and male fertility: Mechanisms, dysregulation, and translational opportunities.

Autophagy is a highly conserved intracellular degradation pathway that plays a central role in maintaining testicular homeostasis and male reproductive function. This review summarises recent advances in the understanding of autophagy in the testis, with particular emphasis on its roles in Sertoli cells, Leydig cells, and germ cells, as well as its regulatory mechanisms and implications for male infertility. Autophagy contributes to key processes, including spermatogenesis, spermiogenesis, blood-testis barrier integrity, and steroidogenesis, through coordinated organelle turnover and cellular remodelling. Core regulatory pathways such as mTOR, AMPK, PI3K/Akt, and oxidative stress-responsive signalling dynamically controls autophagic flux in response to metabolic and environmental cues. Emerging evidence highlights extensive molecular crosstalk between autophagy, apoptosis, ferroptosis, and ubiquitin-mediated proteostasis, with oxidative stress serving as a central upstream regulator. Dysregulation of autophagy, whether through impaired flux or excessive activation, is strongly associated with male infertility phenotypes, including azoospermia, oligozoospermia, and asthenozoospermia. These effects are driven by defects in germ cell development, mitochondrial function, and hormonal balance, and are further exacerbated by environmental toxicants, lifestyle factors, and ageing. Although autophagy-related proteins such as microtubule-associated protein 1 light-chain 3, p62, and Beclin-1 show promise as biomarkers, their clinical application remains limited by challenges in accurately measuring autophagic flux and context-dependent interpretation. Therapeutic modulation of autophagy using pharmacological agents and antioxidants represents a promising but complex strategy that requires precise, context-specific application. Overall, this review underscores the dual role of autophagy in male fertility and highlights the need for improved biomarkers and translational approaches.