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Mechanism of Lenvatinib Resistance via Exosomal miRNA-132/Nrf2 Axis in Hepatocellular Carcinoma

Chie Takasu1, Chiharu Nakasu1, Yu Saito1

  • 1Department of Surgery, Institute of Health Biosciences Tokushima University Tokushima Japan.

Annals of Gastroenterological Surgery
|January 5, 2026
PubMed
Abstract

Insights

Exosomes mediate lenvatinib resistance in hepatocellular carcinoma (HCC) by transferring exosomal miRNA-132. Inhibiting this transfer can overcome chemoresistance and reduce cancer cell proliferation and migration, offering a potential therapeutic strategy for HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Lenvatinib is a first-line targeted therapy for hepatocellular carcinoma (HCC).
  • Acquired resistance limits lenvatinib's efficacy in HCC treatment.
  • Exosomal microRNAs (miRNAs) are implicated in intercellular communication and drug resistance.

Purpose of the Study:

  • To investigate the role of exosomal miRNA exchange in the development of lenvatinib resistance in HCC.
  • To identify specific exosomal miRNAs involved in mediating lenvatinib resistance.
  • To explore the potential of targeting exosomal miRNAs as a therapeutic strategy for overcoming lenvatinib resistance.

Main Methods:

  • Generated lenvatinib-resistant (LVT-res) hepatocellular carcinoma cell lines (Huh7 and PLC).
  • Analyzed miRNA expression profiles in resistant versus parental cells and in exosomes.
  • Co-cultured parental cells with conditioned medium from LVT-res cells to mimic exosomal transfer.
  • Assessed cell proliferation, migration, and chemoresistance.
  • Investigated the PTEN/GSK3β/Nrf2 signaling pathway.

Main Results:

  • Exosomal miRNA-132 was significantly elevated in LVT-res cells.
  • Recipient cells exposed to LVT-res exosomes exhibited increased proliferation, migration, and chemoresistance.
  • The PTEN/GSK3β/Nrf2 signaling pathway was upregulated in recipient cells.
  • Inhibition of exosomal miRNA-132 reversed these effects, reducing malignancy and downregulating the PTEN/GSK3β/Nrf2 pathway.

Conclusions:

  • Exosomal miRNA-132 plays a crucial role in mediating lenvatinib resistance in HCC by promoting cancer cell malignancy and activating the PTEN/GSK3β/Nrf2 pathway.
  • Targeting the miRNA-132/Nrf2 axis presents a potential therapeutic strategy to overcome lenvatinib resistance in HCC.
Keywords:
HCCPTENTME

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