H3K18 lactylation promotes Treg/Th17 imbalance via PTPRM-STAT3 axis in hepatocellular carcinoma
Abstract
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.
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BibTeX
@article{yi2026h3k18,
title = {{H3K18 lactylation promotes Treg/Th17 imbalance via PTPRM-STAT3 axis in hepatocellular carcinoma}},
author = {Jianwei Yi and Zhonghuo Chen and Hengchang Zhu and Rongyuan Liang and Jiafu Guan and Yumin Qiu and Binghai Zhou and Huajun Wu and Xin Yu and Shubing Zou and Kai Wang and Zhigang Hu},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117896},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03279-7},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - H3K18 lactylation promotes Treg/Th17 imbalance via PTPRM-STAT3 axis in hepatocellular carcinoma
AU - Jianwei Yi
AU - Zhonghuo Chen
AU - Hengchang Zhu
AU - Rongyuan Liang
AU - Jiafu Guan
AU - Yumin Qiu
AU - Binghai Zhou
AU - Huajun Wu
AU - Xin Yu
AU - Shubing Zou
AU - Kai Wang
AU - Zhigang Hu
PY - 2026
DA - 2026/10/17
JO - iScience
DO - 10.1016/j.isci.2026.117896
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03279-7
AB - 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.
SN - 2589-0042
ER -