{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T08:55:18Z","timestamp":1790585718468,"version":"4.1.0"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fphar.2026.1930280","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:58:27Z","timestamp":1790582307000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactylation in liver fibrosis: from molecular mechanisms to targeted therapeutic strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhiwei","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Yantai Affiliated Hospital of Shandong Medical and Pharmaceutical University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feibo","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, School of Basic Medicine, Shandong Medical and Pharmaceutical University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Hangzhou First Peoples\u2019 Hospital Xiasha Campus, Hangzhou Rehabilitation Hospital","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Diagnostics, Second School of Clinical Medicine, Shandong Medical and Pharmaceutical University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"104986","DOI":"10.1016\/j.jpet.2026.104986","article-title":"Computational pharmacology and in silico clinical trials for the development of drugs from natural products: a review of advances, opportunities, and challenges","volume":"14","author":"Agbo","year":"2026","journal-title":"J. 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