NBR1-Regulated Mitochondrial Quality Control in Sertoli Cells Is Involved in the Male Reproductive Damage Induced by Chronic Diquat Poisoning, Which Is Ameliorated by Spermidine.

Diquat (DQ) is a widely used herbicide, whose residues have been detected in food products, raising concerns about potential health risks. Nevertheless, the mechanisms underlying male reproductive damage after chronic DQ exposure remain unclear. In this study, we observed that chronic DQ exposure reduces Sertoli cell numbers and triggers mitochondrial quality control (MQC) impairment, oxidative stress, apoptosis, and blood-testis barrier (BTB) disruption in testicular tissue. Mechanistically, DQ downregulates NBR1 in Sertoli cells, leading to impaired mitophagy flux, increased mitochondrial fission, and elevated oxidative stress, which ultimately promote Sertoli cell apoptosis and compromise cellular barrier function. Metabolomic analysis indicated that chronic DQ exposure lowers spermidine (SPD) levels in the mouse testes. Exogenous SPD supplementation attenuated DQ-induced MQC dysfunction, oxidative stress, apoptosis, and BTB damage. Together, these results establish NBR1 as a critical regulator of DQ-triggered Sertoli cell injury and propose SPD as a potential therapeutic candidate for alleviating DQ-induced male reproductive impairment.