P300-mediated H3K56la delactylation promotes copper-induced steroidogenesis disorders in human ovarian granulosa...

As an epigenetic modification, lactylation has attracted widespread attention. Copper (Cu) is an environmental pollutant that has been proven to induce ovarian toxicology. However, the molecular mechanism of lactylation in Cu-related ovarian dysfunction is unclear. In the present study, we demonstrated that Cu exposure disrupted the estrous cycle in animal models and impaired ovarian steroidogenesis in ovarian granulosa cells. Mechanistically, Cu exposure suppressed the levels of steroidogenic factor-1 (SF-1) and inhibited the transcriptional activity of its downstream target, cytochrome P450 family 19 subfamily A member 1 (CYP19A1), a key enzyme in estrogen biosynthesis. Overexpression and knockdown analyses of SF-1 in KGN cells confirmed that SF-1 activated the transcription of CYP19A1. Further investigation revealed that Cu exposure diminishes glycolytic flux by downregulating the levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), consequently decreasing lactate (Lac) production in ovarian granulosa cells. Notably, the levels of p300, a critical histone lactyltransferase, were also reduced. These mechanisms are linked to decreased levels of H3K56 deacetylation, leading to the downregulation of SF-1. Additionally, a vicious cycle involving GAPDH K215la delactylation, which further suppresses Lac production, was identified. Overall, we identified a novel Cu-induced inhibitory mechanism involving both GAPDH K215 delactylation (metabolic level) and p300-mediated H3K56la downregulation (epigenetic level), which synergistically suppressed the SF-1-mediated transcriptional activation of CYP19A1 and impaired steroidogenesis.