Abstract

Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunction, insulin resistance, oxidative stress, and metabolic abnormalities, yet the role of disulfidptosis in granulosa cell injury remains unclear. Here, integrated single-cell and bulk transcriptomic analyses identified granulosa cells as the primary disulfidptosis-associated cell type in the PCOS follicular microenvironment. Disulfidptosis-related genes, including leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), NDUFS1, and OXSM, were significantly downregulated and associated with mitochondrial dysfunction and redox imbalance. A diagnostic model achieved an AUC of 0.867, while Mendelian randomization identified LRPPRC as a protective factor for PCOS. Functionally, LRPPRC deficiency under glucose deprivation induced NADPH depletion, F-actin collapse, and granulosa cell death, which was rescued by 2-mercaptoethanol but not by apoptosis, ferroptosis, or necroptosis inhibitors. In vivo , LRPPRC overexpression improved follicular development and hormonal balance in PCOS mice. These findings identify LRPPRC-mediated disulfidptosis as a potential biomarker and therapeutic target in PCOS.