ArticleJournal of advanced research2025
Long non-coding RNA LINC01532 sustains redox homeostasis and accelerates lenvatinib resistance in hepatocellular carcinoma.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Crosstalk between alternative splicing and non-coding RNAs in hepatocellular carcinoma: from regulatory mechanism to therapeutic implications.Non-coding RNA research · 2026Review
- The lncRNA-m6A axis in cancer: a bidirectional regulatory network in tumor progression and therapeutic resistance.Journal of translational medicine · 2026Review
- The MAFG-AS1/G6PD axis reduces platinum sensitivity in colorectal cancer through pentose phosphate pathway activation.Journal of translational medicine · 2026Article
- A prognostic model utilizing disulfidptosis-related long noncoding RNAs to differentiate pathological grades in hepatocellular carcinoma: functional analysis of AL031985.3.World journal of surgical oncology · 2026Article
- Resistance of first-line targeted drugs in hepatocellular carcinoma: the epigenetic regulation mechanisms.Cell death & disease · 2025Review
- G6PC1 expression as a prognostic biomarker associated with metabolic reprogramming and tumor microenvironment in hepatocellular carcinoma.Frontiers in immunology · 2025Article
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11 authors.
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Abstract
introductionLenvatinib 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.
objectivesThis study aims to delineate the latent mechanism by which HCC cells modulate NADPH metabolic adaptation and lenvatinib resistance.
methodsUsing 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.
resultsHigh 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
conclusionCollectively, 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.
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