As HMGCL catalyzes β-hydroxy-butyric acid (β-OHB) production, we discovered that HMGCL increased acetylation at histone H3K9, which further promoted the transcription of dipeptidyl peptidase 4 (DPP4), a key protein maintains intracellular lipid peroxidation and iron accumulation, leading to HCC cells vulnerability to erastin- and sorafenib-induced ferroptosis. Here, DPP4 is linked to hepatocellular carcinoma.