Mitochondrial PDHA1 acetylation orchestrates lactate-dependent epigenetic reprogramming to promote fibrosis via NUAK2

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with few effective treatment options. While metabolic reprogramming has been associated with IPF, the precise mechanisms connecting mitochondrial metabolic dysfunction to epigenetically driven fibrogenesis remain unclear. In this study, we identify a pathogenic pathway focused on the mitochondrial enzyme pyruvate dehydrogenase E1 alpha subunit (PDHA1). In fibrosis model, downregulation of the deacetylase sirtuin3 (SIRT3) leads to hyperacetylation of PDHA1 at Lys-83. This modification inhibits pyruvate dehydrogenase (PDH) activity, causing a metabolic shift toward glycolysis and increased lactate production. Lactate, in turn, serves as a precursor for the lactylation of histone H4 at K12 (H4K12la), which activates super-enhancer (SE) at the NUAK2 gene locus, significantly enhancing NUAK2 expression. Both genetic and pharmacological inhibition of NUAK2 confirm its role in driving myofibroblast activation and fibrotic progression. Critically, the pro-fibrotic effects of PDHA1 K83 acetylation (K83ac) were reversed by NUAK2 knockdown. Our findings uncover a novel PDHA1 K83ac-H4K12la-NUAK2 pathway that integrates metabolic and epigenetic signals to promote fibrosis, suggesting that targeting PDHA1 deacetylation and inhibiting NUAK2 could be promising therapeutic strategies.