Divergent roles of H3K18 lactylation in human diseases: metabolic-epigenetic circuits and translational challenges

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.