PRDX1 promotes testosterone synthesis and attenuates aging via redox regulation of ATG4B to modulate lipophagy

Testosterone insufficiency disrupts spermatogenesis and expedites male aging. Autophagy facilitates testosterone synthesis. However, a molecular reduction mechanism of autophagy-related protein 4 homolog B (ATG4B) has not been established. Herein, we reveal that peroxiredoxin 1 (PRDX1) is clinically associated with male fertility disorders. Adult mutant mice with Leydig cell (LC)-specific deletion of the Prdx1 gene exhibit premature testicular aging and infertility. A series of in vivo and in vitro experiments, in combination with multi-omics analyses, demonstrate that PRDX1 inactivation impairs lipophagy and testosterone synthesis in LCs. Mechanistically, Cys52 and Cys173 in PRDX1 specifically target the redox-site Cys78 in ATG4B to preserve the delipidating activity of Cys74 in ATG4B, thereby promoting autophagic flux. Furthermore, PRDX1 dysfunction exacerbates testicular and systematic aging in aged mice, which can be alleviated by a 2-cysteine mimic, ebselen. Collectively, our findings demonstrate that PRDX1 promotes lipophagy and testosterone synthesis by regulating ATG4B. Our findings also propose the potential application of ebselen in the prevention and treatment of aging-related disorders, including late-onset hypogonadism.