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AKR1B10 Drives Lenvatinib Resistance in Hepatocellular Carcinoma by Suppressing Ferroptosis via NQO1/GPX4 Axis
Jiahao Jiang1,2, Bingkun Wang1,2, Qingbin Wang1,2
1Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
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 Fe2+ 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.
Insights
AKR1B10 upregulation promotes lenvatinib resistance in hepatocellular carcinoma (HCC) by inhibiting ferroptosis via the NQO1/GPX4 axis. Targeting AKR1B10 may overcome treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC).
- Acquired resistance to lenvatinib significantly limits its clinical efficacy.
- Ferroptosis, a form of regulated cell death, is increasingly recognized for its role in cancer progression and treatment resistance.
Purpose of the Study:
- To investigate the interplay between ferroptosis and lenvatinib resistance in HCC.
- To elucidate the molecular mechanisms underlying lenvatinib resistance in HCC.
- To identify potential therapeutic targets for overcoming lenvatinib resistance.
Main Methods:
- Established a lenvatinib-resistant HCC cell line and employed transcriptome sequencing.
- Validated findings using in vitro (cell viability, colony formation, apoptosis) and in vivo (xenograft models) assays.
- Analyzed ferroptosis using TEM, C11-BODIPY staining, MDA measurement, and Fe2+ detection; explored mechanisms via KEGG analysis, Western blotting, and immunofluorescence.
Main Results:
- AKR1B10 was upregulated in lenvatinib-resistant HCC cells and inhibited lenvatinib-induced ferroptosis.
- Knockdown of AKR1B10 reversed acquired lenvatinib resistance and restored ferroptosis.
- The NQO1/GPX4 axis was identified as the downstream pathway mediating AKR1B10's regulation of ferroptosis.
Conclusions:
- AKR1B10 promotes acquired lenvatinib resistance in HCC by suppressing ferroptosis through the NQO1/GPX4 signaling pathway.
- AKR1B10 represents a potential novel therapeutic target for overcoming lenvatinib resistance in HCC.
