ArticleJournal of gastrointestinal oncology2026
Targeting AKR1C1 overcomes lenvatinib resistance in hepatocellular carcinoma through the STAT3-ABC transporters pathway.
Article in Journal of gastrointestinal oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related deaths worldwide. Lenvatinib, a widely used treatment, often has its efficacy limited by acquired resistance. Accumulating evidence indicates that the aldo-keto reductase 1 (AKR1) family plays a key role in tumor treatment resistance. This study aims to explore the mechanism of AKR1 family regulating lenvatinib resistance and identify new drugs to overcome it. Methods: The establishment of lenvatinib-resistant HCC cells (HuH7/R and Hep3B/R) was achieved through long-term exposure to lenvatinib. The expression of the AKR1 family genes in these cells was identified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Plasma AKR1C1 was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of AKR1C1 on lenvatinib-resistant HCC cells was assessed by transfecting small interfering RNA (siRNA) and the AKR1C1 inhibitor, flufenamic acid (FFA). The mechanism by which AKR1C1 regulates lenvatinib resistance in liver cancer cells was investigated through the application of co-immunoprecipitation and signaling pathway inhibitor assays. Results: AKR1C1, a member of the AKR1 family, was overexpressed in lenvatinib-resistant HCC cells and in the plasma of lenvatinib-resistant HCC patients. Bioinformatics studies revealed that high AKR1C1 mRNA expression was linked to a less favourable prognosis in HCC patients. The transfection of siRNA-AKR1C1 can overcome lenvatinib resistance. Mechanistically, AKR1C1 was demonstrated to interact with and activate STAT3, which in turn upregulated the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), thereby conferring lenvatinib resistance. AKR1C1 inhibitor FFA, a non-steroidal anti-inflammatory drug, effectively reversed lenvatinib resistance, restricting the growth of lenvatinib-resistant HCC cells. Conclusions: AKR1C1 may drive lenvatinib resistance in HCC by activating the STAT3-ATP-binding cassette (ABC) transporters pathway, thereby providing both a potential predictive biomarker and a therapeutic target for intervention.
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