H3K18 lactylation promotes Treg/Th17 imbalance via PTPRM-STAT3 axis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) exhibits elevated lactate levels and Treg/Th17 imbalance, but underlying mechanisms remain unclear. We found that HCC patients show increased serum lactate correlated with expanded Tregs and reduced Th17 cells. Lactate treatment promoted FOXP3 while suppressing RORγt in vitro. Western blot revealed significantly elevated histone lactylation in HCC PBMCs, with H3K18la showing the most pronounced increase. Genome-wide H3K18la profiling by CUT&Tag identified global epigenetic reprogramming at immune-related loci. Integrating epigenomic and transcriptomic data revealed PTPRM as a key gene with enhanced H3K18la enrichment and elevated expression. H3K18la enrichment at the PTPRM locus was significantly increased in HCC samples compared with controls, whereas treatment with the LDHA inhibitor oxamate markedly reduced this enrichment. PTPRM knockdown decreased Tregs, increased Th17 cells, and promoted STAT3 Y705 phosphorylation in vitro and in a murine HCC model. Targeting this lactate-H3K18la-PTPRM axis may offer valuable therapeutic strategies for HCC.