miR ‐486‐3p knockdown induces testicular ferroptosis by upregulating Acsl4 in mice: a novel molecular target for non‐lethal fertility control of rodent pests

BACKGROUND: Rodent population outbreaks pose serious threats to public health and agricultural production. Traditional lethal rodenticides can cause environmental contamination and poisoning of nontarget organisms, while raising animal welfare concerns, creating an urgent demand for environmentally friendly, nonlethal control strategies. Fertility control through intervention at key molecular targets enables population regulation while preserving ecological integrity, making it a promising nonlethal alternative. Ferroptosis-mediated impairment of testicular function provides a theoretical basis for male fertility control. Nevertheless, key regulatory targets in this pathway remain poorly defined. Here, we used mice as a model to investigate a potential molecular target for inducing male reproductive impairment, laying the foundation for future applications in rodent pest population control. RESULTS: We found that miR-486-3p targets the ferroptosis-associated gene encoding acyl-CoA synthetase long-chain family member 4 (Acsl4) and inhibits its expression. miR-486-3p overexpression alleviated peroxide accumulation induced by RAS selective lethal 3 in Sertoli cells and testicular tissue, reducing sensitivity to ferroptosis and indicating that miR-486-3p plays a critical role in regulating ferroptosis. Local knockdown of miR-486-3p in the testis induced peroxide accumulation and ferroptosis, disrupted the seminiferous tubule structure, and caused a 10.8% reduction in testicular weight and a 78.2% reduction in epididymal sperm count. CONCLUSION: Our results suggest that miR-486-3p knockdown induces ferroptosis-associated testicular damage by upregulating Acsl4, providing a candidate target for developing nonlethal interventions for rodent pest population management via male fertility control.