Stearoyl-CoA desaturase 1-mediated lipid metabolic reprogramming in granulosa cells contributes to follicular dysfunction in non-overweight polycystic ovary syndrome patients.

In women of reproductive age, polycystic ovary syndrome (PCOS) is a widespread endocrine condition that is primarily connected to disrupted lipid metabolism. However, the cell-specific lipidomic signatures and their regulatory mechanisms in ovarian granulosa cells (GCs) of PCOS women remain elusive, particularly across clinical subgroups. We conducted quantitative lipidomics to profile luteinized GC lipid metabolism in PCOS subgroups. Non-overweight PCOS (NOP) patients underwent targeted validation via qRT-PCR and western blotting for lipid metabolism markers. Mechanistic studies employed SCD1-silenced human GC lines and a GC-specific SCD1 knockout mouse model, incorporating long-term fertility assessments. GCs from PCOS women, especially the NOP subgroup, displayed a unique lipidomic signature marked by suppressed biosynthesis and enhanced degradation, contrasting with circulating lipid profiles. Clinically, SCD1 expression correlated with improved embryo quality and implantation rates. In vitro, SCD1 deficiency triggered GC metabolic dysfunction, featuring reduced lipogenesis, elevated lipid peroxidation, iron accumulation, and mitochondrial impairment, which are characteristic of ferroptosis. In vivo, the GC-specific SCD1 deletion model exhibited an accumulation of secondary follicles, increased atresia, and progressive subfertility, alongside disrupted expression of lipid and iron metabolic regulators. Our study provides an integrated evidence chain suggesting that SCD1 acts as a regulator of lipid homeostasis in GCs. SCD1 deficiency contributes to metabolic disturbances that disrupt folliculogenesis, providing a potential mechanistic basis for the subtype-specific follicular dysfunction observed in NOP patients.