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. Here, HOXB13 is linked to hepatocellular carcinoma.