In summary, these results revealed a lipid metabolism-related and relatively liver-specific lncRNA HNF4A-AS1 inhibits sorafenib resistance in HCC, by promoting METTL3/m6A/YTHDF3-mediated DECR1 mRNA degradation, leading to intracellular PUFA accumulation, and subsequently, sorafenib-induced ferroptosis. The gene discussed is METTL3; the disease is hepatocellular carcinoma.