Mitochondrial PDHA1 acetylation orchestrates lactate-dependent epigenetic reprogramming to promote fibrosis via NUAK2 - PubMed
5 days ago
- #Epigenetics
- #Fibrosis
- #Metabolism
- Mitochondrial PDHA1 acetylation at Lys-83 inhibits PDH activity, leading to increased glycolysis and lactate production.
- Lactate serves as a precursor for histone H4 lactylation at K12 (H4K12la), activating super-enhancers at the NUAK2 gene locus.
- NUAK2 overexpression drives myofibroblast activation and fibrotic progression, confirmed by genetic and pharmacological inhibition.
- PDHA1 K83ac-H4K12la-NUAK2 pathway integrates metabolic and epigenetic signals to promote fibrosis.
- Targeting PDHA1 deacetylation and NUAK2 inhibition are proposed as potential therapeutic strategies for idiopathic pulmonary fibrosis (IPF).