Lactate promotes liver regeneration by increasing fatty acid oxidation through GCN5-mediated H3K9 lactylation.
BACKGROUND & AIMS Lactylation has been implicated in the repair and regeneration of multiple organs including skin and heart. The liver serves as a vital organ for lactate metabolism, while the roles of lactate and lactylation during liver regeneration remain unclear. METHODS Mice were subjected to 70% partial hepatectomy (PHx), and liver-to-body weight (LW/BW) ratio and proliferative markers were measured. Protein-protein interactions were detected by Co-IP. The pivotal site of GCN5 for catalysis was predicted by theoretical modelling. CUT&Tag and bulk RNA-seq assays were used to identify downstream genes regulated by H3K9 lactylation (H3K9la). Murine hepatocyte organoids and human liver tissues were used to validate the effects of H3K9la. RESULTS Lactate supplementation notably improved LW/BW ratio and upregulated hepatic levels of Ki-67, PCNA and EdU incorporation at 48 h after PHx, while hepatocyte-specific Ldha knockout mice showed impaired liver regenerative capacity. In vitro experiments indicated that increased intracellular lactate upregulated H3 lactylation and promoted hepatocyte proliferation. Mechanistically, GCN5, rather than P300 or MOF, was identified as the pivotal enzyme catalyzing H3K9la. Furthermore, lactate treatment promoted the interaction between GCN5 and H3K9 during liver regeneration. Glu639 was identified as the critical amino acid residue in GCN5 for catalyzing H3K9la. CUT&Tag and bulk RNA-seq results further revealed that H3K9la upregulated the expression of Lipin1 and its mediated transcription of fatty acid oxidation (FAO)-related genes. The pro-regenerative effects of lactate and H3K9la were validated using murine hepatocyte organoids and human liver tissues. CONCLUSIONS Lactate facilitates liver regeneration through promoting GCN5-mediated H3K9la, which upregulates Lipin1 transcription and subsequent Lipin1-mediated FAO in hepatocytes.