Lactylation in liver fibrosis: from molecular mechanisms to targeted therapeutic strategies.

Metabolic reprogramming and epigenetic remodeling of hepatic stellate cells (HSCs) represent central driving events in liver fibrosis. Lactylation, a lactate-mediated post-translational modification (PTM), is proposed to converge on histone H3 lysine 18 lactylation (H3K18La) through the HK2-KAT8 positive feedback loop, the IGF2BP2-N6-methyladenosine (m6A)-aldolase A (ALDOA) cascade, and the HKDC1-ORMDL3 pathway, potentially driving pro-fibrotic transcriptional programs in a synergistic manner. H3K18La does not operate in isolation; its site-specific competition with acetylation, cascade amplification with m6A methylation, cooperation with G9a/DNMT1-mediated methylation, and antagonism with ubiquitination form a PTM interaction network. Therapeutically, interventions targeting lactate-metabolizing enzymes (HK2, LDH), lactylation writers (KAT8), and specific lactylation sites (PGK1-K353 interfering peptides) have demonstrated anti-fibrotic potential in preclinical models. Natural products including curcumol, limonin, and salidroside exhibit multi-target regulatory advantages. Muscle-derived SORBS3 lactylation-mediated trans-organ signaling and lactylation gene-based molecular subtyping expand the systemic dimensions of lactylation. This narrative review proposes a working hypothesis positioning H3K18La as a metabolic-epigenetic convergence node and outlines future directions including site-specific interventions, cell type-resolved lactylomics, and molecular subtyping-driven clinical trials, providing an integrated framework from basic research to translational applications for liver fibrosis.