INTRODUCTION: Lenvatinib is the first-line therapy of hepatocellular carcinoma (HCC) and the high frequency of lenvatinib resistance hinders the improvement of HCC treatment. Since NADPH plays vital roles in antioxidant defense and reductive biosynthesis, cancer cells exert NADPH metabolic adaptation to support their malignant activities, including drug resistance. However, the underlying mechanisms need to be further studied. OBJECTIVES: This study aims to delineate the latent mechanism by which HCC cells modulate NADPH metabolic adaptation and lenvatinib resistance. METHODS: Using high-throughput screening, we screened LINC01532 as a critical regulator in NADPH metabolic adaptation. The function of LINC01532 in drug resistance of HCC cells was analyzed by in vitro and in vivo model. NADPH assay, malondialdehyde (MDA) assay, and glutathione (GSH) detection assay were carried out to explore the role of LINC01532 in NADPH metabolism. Furthermore, RNA-binding protein immunoprecipitation, RNA pull-down assay, co-immunoprecipitation, and chromatin immunoprecipitation experiments were utilized to uncover the underlying mechanisms. RESULTS: High expression of LINC01532 predicted poorer prognosis in HCC patients. LINC01532 stimulated NADPH production and blunted lenvatinib-induced cell death, leading to drug resistance. Mechanistically, LINC01532 bound to hnRNPK and promoted CDK2-mediated phosphorylation of hnRNPK, which facilitated G6PD pre-mRNA splicing, resulting in high expression of G6PD and upregulated NADPH synthesis. The elevated NADPH cleared reactive oxygen species (ROS), supported biomass synthesis, and epigenetically modulated gene expression. Inhibition of LINC01532 significantly enhanced lenvatinib sensitivity of HCC cells. The m CONCLUSION: Collectively, our findings demonstrate that LINC01532 confers lenvatinib resistance of HCC cells by modulating NADPH metabolic adaptation. LINC01532 might be a prognostic or therapeutic target for HCC.