Background: Resistance to sorafenib remains a major challenge in the systemic therapy of liver cancer. However, the involvement of lipid metabolism-related lncRNAs in this process remains unclear. Methods: Different expression levels of lipid metabolism-related lncRNAs in HCC were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The influence of HNF4A-AS1 on sorafenib response was evaluated through analysis of public biobanks, cell cytotoxicity and colony formation assays. The effect of HNF4A-AS1 on sorafenib-induced ferroptosis was measured using lipid peroxidation, glutathione, malondialdehyde, and ROS levels. Furthermore, bioinformatic analyses and lipidomic profiling were conducted to study HNF4A-AS1 involvement in lipid metabolic reprogramming. Mechanistic experiments, including the luciferase reporter assay, RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and RNA remaining assays, were employed to uncover the downstream targets and regulatory mechanisms of HNF4A-AS1 in sorafenib resistance in HCC. Xenograft and organoid experiments were carried out to assess the impact of HNF4A-AS1 on sorafenib response. Results: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC. Conclusions: Our results indicated the pivotal role of lipid metabolism-related and liver-specific HNF4A-AS1 in inhibiting sorafenib resistance by promoting ferroptosis and suggesting that HNF4A-AS1 might be a potential target for HCC.

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