CD36-driven mtDNA release activates cGAS-STING to induce lipotoxic senescence in granulosa cells: a metabolic-inflammatory nexus in PCOS follicular arrest

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility and is inseparably linked to metabolic dysfunction. Follicular arrest—the central pathological hallmark—associates with granulosa cell (GC) senescence; however, the metabolic triggers and therapeutic leverage points remain undefined. Here, we identify lipotoxicity-induced cellular senescence as a fundamental driver of ovarian dysfunction in PCOS. GCs from 35 patients with PCOS and 35 age-matched controls were analyzed. In vitro, palmitic acid (PA)-exposed KGN cells and a letrozole/high-fat-diet PCOS mouse model were used to dissect the CD36-mtDNA-cGAS-STING axis and evaluate the efficacy of nicotinamide mononucleotide (NMN). Analysis of follicular fluid from metabolically compromised patients with PCOS revealed elevated triglycerides strongly correlated with inflammatory markers. GCs from these patients exhibited pathological lipid accumulation, cytosolic mtDNA release, cGAS-STING pathway activation, and senescence markers (SA-β-gal positivity, p53/p21 upregulation), without telomere attrition. Mechanistically, CD36 upregulation triggered a PPARγ-FABP3 transcriptional cascade that disrupted mitochondrial integrity, promoting mtDNA release and cGAS-STING-dependent SASP secretion. This lipotoxic senescence program was reproduced in vitro using palmitic acid-treated GCs and reversed by genetic or pharmacological inhibition of CD36, PPARγ, FABP3, or STING. Critically, PCOS GCs exhibited NAD + depletion, which was rescued by nicotinamide mononucleotide (NMN). NMN suppressed the CD36 axis, prevented mtDNA release, and reversed cellular senescence. In vivo , STING inhibition, CD36 blockade, and particularly NAD + repletion with NMN rescued ovarian function in a letrozole/high-fat diet-induced PCOS mouse model, reducing cystic follicles and restoring ovulation. Lipotoxicity drives GC senescence through the CD36-mtDNA axis, thereby enforcing follicular arrest via proliferative blockade and SASP-mediated inflammation. NAD + repletion with NMN reinstates redox homeostasis, reverses GC senescence and reinstates ovarian function.