Resistance to first-line multikinase inhibitors (MKIs) sorafenib and lenvatinib critically limits hepatocellular carcinoma (HCC) treatment efficacy.It remains largely unknown how long non-coding RNAs (lncRNAs) affect resistance to MKIs.Through integrated analysis of resistant HCC models, we identified lncRNA LMCD1-AS1 as a critical driver of MKI resistance.LMCD1-AS1 overexpression correlates with advanced tumor stage, shortened survival, and resistance to MKI therapy in HCC patients.LMCD1-AS1 confers dual resistance to sorafenib and lenvatinib by suppressing apoptosis, while its knockdown restored drug sensitivity.Mechanistically, LMCD1-AS1 directly bind histone demethylase PHF8, promoting H4K20me1 to epigenetically activate oncogenes (e.g., c-Myc, -catenin) and upregulate lactate dehydrogenase A (LDHA).This triggers lactate overproduction and alters the NAD + /NADH ratio, establishing a protumorigenic metabolic state.Crucially, PHF8 ablation reverses LMCD1-AS1-driven resistance, and in vivo xenografts confirm attenuated sorafenib efficacy with LMCD1-AS1 overexpression.Our work unveils the LMCD1-AS1/PHF8/H4K20me1 axis as a unified epigenetic-metabolic mechanism underlying MKI resistance, representing a promising therapeutic target and prognostic biomarker for HCC.
Yang et al. (Mon,) studied this question.