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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, β-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.