SIRT1 deacetylates PKM2 to constrain lactate production and protect against premature ovarian insufficiency

Abstract Premature ovarian insufficiency (POI) causes early loss of ovarian function, though its underlying metabolic-epigenetic mechanisms remain unclear. Using ovarian tissues from POI patients and a cisplatin-induced mouse model, we investigated the role of the NAD+-dependent deacetylase Sirtuin 1 (SIRT1) in granulosa cells. We found that SIRT1 expression was markedly downregulated in POI, correlating with hyperacetylation of the glycolytic enzyme pyruvate kinase M2 (PKM2) and pathogenic lactate accumulation. Restoring SIRT1 activity via intra-ovarian AAV-SIRT1 delivery or systemic administration of nicotinamide mononucleotide (NMN) reversed these phenotypes. This intervention improved follicular development, reduced granulosa cell apoptosis, and normalized serum anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) levels. Mechanistically, SIRT1 directly interacts with and deacetylates PKM2, suppressing its activity and limiting lactate production. Our work defines a critical SIRT1–PKM2–lactate metabolic axis that maintains ovarian homeostasis. Targeting this axis via NAD+-boosting interventions, such as NMN, presents a promising novel therapeutic strategy for POI.