Divergent roles of H3K18 lactylation in human diseases: metabolic-epigenetic circuits and translational challenges
- 1epartment of Pathology, Affiliated Hospital of Nantong University, Nantong, China
Abstract
Histone H3 lysine 18 lactylation (H3K18la) links fluctuations in lactate metabolism with chromatin-dependent transcription. Promoter- and enhancer-level associations suggest that H3K18la can report local metabolic-chromatin coupling, but evidence for modification-specific causality remains uneven because the known writers and erasers are promiscuous, dedicated readers are poorly defined, and broad acyltransferase inhibitors perturb competing histone and non-histone marks. Across tumor, inflammatory, metabolic, cardiovascular, and degenerative-disease models, H3K18la participates in oncogenic, immunoregulatory, fibrotic, or reparative programs according to cell lineage, chromatin state, metabolic exposure, and disease stage. We synthesize these observations using a testable framework in which lactate and lactyl-CoA provide metabolic permission, whereas transcription factors, chromatin accessibility, histone chaperones, and candidate protein or RNA scaffolds provide locus selection; downstream readers or conventional transcriptional effectors then shape the biological output. Direct long non-coding RNA (lncRNA)-guided deposition and a universally validated H3K18la reader remain unproven. Human cohort data support exploratory, disease-specific associations, but assay heterogeneity and the lack of prospective external validation preclude current clinical use. Progress will require histone H3 lysine 18 acetylation (H3K18ac)-aware, inhibitor-independent causal tests, structural validation of readers, integrated chromatin-RNA profiling, and prospective multicenter cohorts.
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BibTeX
@article{wu2026divergent,
title = {{Divergent roles of H3K18 lactylation in human diseases: metabolic-epigenetic circuits and translational challenges}},
author = {Ting Wu and Yali Zhang and Yifei Liu},
journal = {Frontiers in Genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1950620},
url = {https://doi.org/10.3389/fgene.2026.1950620},
note = {CC BY},
}
RIS
TY - JOUR
TI - Divergent roles of H3K18 lactylation in human diseases: metabolic-epigenetic circuits and translational challenges
AU - Ting Wu
AU - Yali Zhang
AU - Yifei Liu
PY - 2026
DA - 2026/10/26
JO - Frontiers in Genetics
DO - 10.3389/fgene.2026.1950620
UR - https://doi.org/10.3389/fgene.2026.1950620
AB - Histone H3 lysine 18 lactylation (H3K18la) links fluctuations in lactate metabolism with chromatin-dependent transcription. Promoter- and enhancer-level associations suggest that H3K18la can report local metabolic-chromatin coupling, but evidence for modification-specific causality remains uneven because the known writers and erasers are promiscuous, dedicated readers are poorly defined, and broad acyltransferase inhibitors perturb competing histone and non-histone marks. Across tumor, inflammatory, metabolic, cardiovascular, and degenerative-disease models, H3K18la participates in oncogenic, immunoregulatory, fibrotic, or reparative programs according to cell lineage, chromatin state, metabolic exposure, and disease stage. We synthesize these observations using a testable framework in which lactate and lactyl-CoA provide metabolic permission, whereas transcription factors, chromatin accessibility, histone chaperones, and candidate protein or RNA scaffolds provide locus selection; downstream readers or conventional transcriptional effectors then shape the biological output. Direct long non-coding RNA (lncRNA)-guided deposition and a universally validated H3K18la reader remain unproven. Human cohort data support exploratory, disease-specific associations, but assay heterogeneity and the lack of prospective external validation preclude current clinical use. Progress will require histone H3 lysine 18 acetylation (H3K18ac)-aware, inhibitor-independent causal tests, structural validation of readers, integrated chromatin-RNA profiling, and prospective multicenter cohorts.
SN - 1664-8021
ER -