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Targeting AKR1C1 overcomes lenvatinib resistance in hepatocellular carcinoma through the STAT3-ABC transporters

Yue Zhang1, Lu Zheng1,2, An-Qiang Feng3

  • 1Department of Clinical Laboratory, Xuzhou Institute of Medical Science, Xuzhou Central Hospital, Southeast University, Xuzhou, China.

Journal of Gastrointestinal Oncology
|May 22, 2026
PubMed
Abstract

Insights

Aldo-keto reductase 1C1 (AKR1C1) drives lenvatinib resistance in hepatocellular carcinoma (HCC) by activating STAT3 and drug efflux pumps. Inhibiting AKR1C1 with flufenamic acid (FFA) can overcome this resistance, offering a new therapeutic strategy for HCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally.
  • Lenvatinib resistance significantly limits treatment efficacy in HCC.
  • The aldo-keto reductase 1 (AKR1) gene family is implicated in acquired treatment resistance.

Purpose of the Study:

  • To elucidate the mechanism by which AKR1 family members mediate lenvatinib resistance in HCC.
  • To identify potential therapeutic targets for overcoming lenvatinib resistance in HCC.
  • To evaluate novel drug strategies for enhancing lenvatinib efficacy.

Main Methods:

  • Established lenvatinib-resistant HCC cell lines (HuH7/R, Hep3B/R).
  • Quantified AKR1 gene expression via qRT-PCR and AKR1C1 plasma levels via ELISA.
  • Assessed AKR1C1's role using siRNA and the inhibitor flufenamic acid (FFA).
  • Investigated molecular mechanisms via co-immunoprecipitation and pathway inhibition assays.

Main Results:

  • AKR1C1 was overexpressed in resistant HCC cells and patient plasma, correlating with poor prognosis.
  • siRNA-mediated AKR1C1 knockdown reversed lenvatinib resistance.
  • AKR1C1 activated STAT3, upregulating MDR1, MRP2, and BCRP, conferring resistance.
  • FFA treatment effectively reversed lenvatinib resistance and inhibited tumor growth.

Conclusions:

  • AKR1C1 drives lenvatinib resistance in HCC via the STAT3-ABC transporter pathway.
  • AKR1C1 serves as a potential predictive biomarker for lenvatinib resistance.
  • Targeting AKR1C1 presents a promising therapeutic strategy for overcoming lenvatinib resistance in HCC.
Keywords:
AKR1C1Hepatocellular carcinoma (HCC)flufenamic acid (FFA)lenvatinib resistance

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