Homeobox B13 activates the hypoxia‐inducible factor 1 pathway through histone lactylation thereby reprogramming lipid metabolism and promoting sorafenib resistance in hepatocellular carcinoma

Resistance of hepatocellular carcinoma (HCC) to sorafenib represents a major clinical challenge, involving complex metabolic alterations and epigenetic regulatory changes. However, the underlying mechanisms remain incompletely understood. In this study, we found that the level of histone H3 lysine 18 lactylation (H3K18la), derived from lactate, was significantly elevated in sorafenib-resistant HCC cells. Mechanistically, using Micrococcal Nuclease-Chromatin Immunoprecipitation-quantitative Polymerase Chain Reaction and related techniques, we demonstrated that H3K18la is directly enriched at the promoter region of homeobox B13 (HOXB13) and functions as a potent transcriptional activator to upregulate its expression. Further mechanistic investigations revealed that HOXB13 stabilizes hypoxia-inducible factor-1α (HIF-1α) protein expression, thereby activating the HIF-1 signaling pathway, promoting lipid metabolism reprogramming, and enhancing lipid accumulation. Functional experiments demonstrated that the inhibition of H3K18la or knockdown of HOXB13 effectively reversed lipid accumulation and significantly increased cellular sensitivity to sorafenib. This study systematically delineates a signaling cascade (the H3K18la-HOXB13-HIF-1 axis) spanning metabolites, epigenetic modifications, transcriptional regulation, and downstream metabolic phenotypes, thereby deepening our understanding of tumor drug resistance mechanisms and providing potential therapeutic targets for overcoming HCC resistance to sorafenib.