Nicotinamide mononucleotide supplementation improves polycystic ovary syndrome by activating silent regulatory protein 2 mediated lactate dehydrogenase A lysine 119 deacetylation to enhance glycolytic activity.

BACKGROUND

Polycystic ovary syndrome (PCOS) is associated with impaired granulosa cell (GC) glycolytic activity. Although lactate dehydrogenase A (LDHA)-a key glycolytic enzyme modulated by acetylation-is involved, its regulatory mechanism remains unclear. This study investigated whether nicotinamide mononucleotide (NMN) alleviates PCOS by promoting LDHA deacetylation to enhance glycolytic function.

METHODS

We established a PCOS rat model via letrozole (1 mg/kg/d) gavage combined with high-fat diet for 30 days; after successful modeling, rats were randomly assigned to receive either vehicle or NMN (500 mg/kg/d) for an additional 30 days..We then evaluated metabolic phenotypes, reproductive hormone profiles, ovarian histopathology, and estrous cycle regularity. The underlying molecular mechanism was verified in testosterone (10 μM)-treated human granulosa-like KGN cells via a series of molecular assays including qRT-PCR, western blotting, co-immunoprecipitation (Co-IP), and site-directed mutagenesis.

RESULTS

NMN supplementation significantly reversed insulin resistance, hyperandrogenism, estrous cycle disorder, and polycystic ovarian morphology in PCOS rats, and simultaneously increased ovarian NAD+ levels and glycolytic activity. We further identified SIRT2 as the specific deacetylase of LDHA, and uncovered K119 as the key functional acetylation site that regulates LDHA enzymatic activity. Mechanistically, NMN promoted SIRT2-mediated deacetylation of LDHA at K119, which enhanced glycolytic activity, promoted proliferation, and inhibited apoptosis in ovarian GCs.

CONCLUSION

Our findings demonstrate that NMN enhances glycolytic activity in ovarian GCs via the SIRT2/LDHA-K119 regulatory axis, thereby ameliorating PCOS-related reproductive and metabolic disorders. Collectively, these findings identify the SIRT2-LDHA axis as a novel therapeutic target and provide preclinical evidence supporting NMN as a potential intervention for PCOS.