Chronic sleep deprivation induces ovarian ferroptosis and premature ovarian insufficiency linked to IL-17 signaling.

OBJECTIVE: Sleep deprivation (SD) disrupts female reproductive homeostasis, yet the mechanisms linking chronic sleep loss to premature ovarian insufficiency (POI) remain poorly defined. METHODS: We analyzed sleep patterns and menopause timing in 147,814 UK Biobank women using multivariable logistic regression. We established a chronic SD mouse model and performed integrated multi-omics profiling, including serum proteomics and ovarian RNA sequencing, with pharmacological rescue using the ferroptosis inducer Erastin and inhibitor Ferrostatin-1. RESULTS: Healthier sleep patterns were associated with reduced premature menopause risk (OR = 0.466, 95% CI: 0.263-0.826 for highest vs. lowest score). SD mice showed disrupted estrous cyclicity, elevated FSH, decreased AMH and E2, and accelerated ovarian reserve depletion. Multi-omics analysis revealed systemic inflammation (elevated IL-1α and IL-6) and ovarian enrichment of the IL-17 and ferroptosis pathways. Erastin recapitulated major SD-induced ovarian defects, whereas Ferrostatin-1 partially rescued the phenotype, establishing ferroptosis as a critical mediator. IL-17A and IL-17RA were upregulated and co-localized with ferroptosis markers in the ovarian stroma, nominating IL-17 signaling as a candidate upstream regulator. CONCLUSION: Our findings establish ovarian ferroptosis as a key pathogenic mechanism linking chronic sleep deprivation to POI, and highlight sleep quality as a modifiable factor for preserving ovarian health.