Melatonin Alleviates Sleep Disturbance-Induced Ovarian Reserve Decline by Suppressing NLRP3-Mediated Pyroptosis in Granulosa Cells

Abstract

Sleep disturbance perturbs circadian and immune homeostasis and is increasingly associated with female reproductive dysfunction, yet the underlying cellular mechanisms remain unclear. Here, we identify granulosa cell pyroptosis as a central mechanism linking sleep disturbance to ovarian reserve decline. Mendelian randomization analyses support an association between frequent sleep disorders and ovarian dysfunction, consistent with clinical evidence of reduced ovarian reserve in women with poor sleep quality. Mechanistically, sleep disturbance induces a pro-inflammatory ovarian microenvironment characterized by oxidative stress, activation of the NLRP3 inflammasome, and pyroptotic death of granulosa cells, accompanied by ultrastructural damage. Melatonin, a key circadian regulator and a potent antioxidant, suppresses NLRP3-mediated pyroptosis, alleviates oxidative stress, and preserves granulosa cell integrity. In a randomized clinical setting, melatonin supplementation partially restores ovarian reserve markers and improves reproductive outcomes. These findings define an inflammation-driven pyroptotic pathway underlying sleep disturbance–induced ovarian dysfunction and establish melatonin as a mechanistic modulator of ovarian inflammasome activation, supporting circadian-targeted strategies for preserving female reproductive health.