AKR1B10 Drives Lenvatinib Resistance in Hepatocellular Carcinoma by Suppressing Ferroptosis via NQO1/GPX4 Axis

ABSTRACT Background Lenvatinib is utilized as a first‐line therapy for hepatocellular carcinoma (HCC); however, the emergence of resistance significantly impairs its clinical efficacy. Ferroptosis, a newly recognized form of cell death, has been implicated in tumor progression and treatment resistance. This study investigates the interaction between ferroptosis and lenvatinib resistance in HCC and explores the underlying mechanisms. Methods A lenvatinib‐resistant cell line was established, combined with multiplex transcriptome sequencing and external bioinformatics analysis to identify key resistance genes. The biological functions of lenvatinib resistance were validated through assays of cell viability, colony formation, apoptosis, and xenograft models. Ferroptosis effects were analyzed using assays such as transmission electron microscopy (TEM), C11‐BODIPY staining, malondialdehyde (MDA) measurement, and Fe 2+ detection. Furthermore, KEGG pathway enrichment analysis, Western blotting, immunofluorescence colocalization, and immunohistochemistry were conducted to explore the underlying mechanisms. Results Transcriptome sequencing combined with in vitro and in vivo experiments revealed that AKR1B10 was significantly downregulated following short‐term lenvatinib treatment, but was upregulated with the induction of resistance. Knockdown of AKR1B10 markedly reversed acquired resistance to lenvatinib. Furthermore, we found that the upregulation of AKR1B10 substantially inhibited lenvatinib‐induced ferroptosis. Mechanistically, the NQO1/GPX4 axis was identified as the downstream signaling pathway through which AKR1B10 regulates ferroptosis. Notably, overexpression of NQO1 effectively restored both ferroptosis and sensitization to lenvatinib induced by AKR1B10 knockdown. Conclusions This study reveals that AKR1B10 inhibits ferroptosis in HCC through the NQO1/GPX4 axis, promoting acquired resistance to lenvatinib. These findings suggest that AKR1B10 could be a novel therapeutic target for overcoming lenvatinib resistance.