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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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DNMT2-m5C-ACLY Axis Promotes Lenvatinib Resistance in Hepatocellular Carcinoma Through Histone Acetylation-Mediated

Shiguang Yang1,2, Jie Li3, Shengwei Mao1

  • 1Department of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 19, 2025
PubMed

Insights

Drug resistance to lenvatinib in liver cancer (HCC) can be overcome by targeting DNA methyltransferase 2 (DNMT2). Downregulating DNMT2 restores sensitivity by inhibiting the DNMT2-ACLY-NOTCH pathway, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lenvatinib is a first-line treatment for advanced hepatocellular carcinoma (HCC).
  • Acquired drug resistance limits lenvatinib's clinical efficacy.
  • Identifying targets to reverse lenvatinib resistance is crucial for improved treatment outcomes.

Purpose of the Study:

  • To investigate the mechanisms underlying lenvatinib resistance in HCC.
  • To identify novel therapeutic targets for overcoming lenvatinib resistance.
  • To evaluate the potential of targeting the DNMT2-ACLY-NOTCH axis for HCC treatment.

Main Methods:

  • Global m5C modification levels were analyzed in lenvatinib-resistant HCC cells.
  • DNA methyltransferase 2 (DNMT2) expression was assessed in resistant specimens.
  • In vitro and in vivo experiments were conducted to evaluate the effect of DNMT2 downregulation.
  • The interaction between DNMT2, Y-box binding protein 1 (YBX1), and adenosine triphosphate citrate lyase (ACLY) mRNA was investigated.
  • Notch signaling pathway activation and its relation to intracellular acetyl-CoA and histone acetylation were studied.
  • Pharmacological inhibition of ACLY in combination with lenvatinib was evaluated in preclinical models.

Main Results:

  • Lenvatinib-resistant HCC cells exhibited elevated m5C modification levels.
  • DNMT2 was upregulated in resistant specimens and correlated with poor survival.
  • DNMT2 downregulation restored sensitivity to lenvatinib by reducing proliferation and promoting apoptosis.
  • DNMT2 stabilized ACLY mRNA via m5C modification, activating the Notch pathway.
  • Combined inhibition of ACLY and lenvatinib treatment reduced tumor burden in preclinical models.

Conclusions:

  • The DNMT2-ACLY-NOTCH signaling axis plays a critical role in lenvatinib resistance in HCC.
  • DNMT2 downregulation is a promising strategy to overcome lenvatinib resistance.
  • Combinatorial therapy targeting ACLY and lenvatinib offers a potential new approach for HCC treatment.
Keywords:
hepatocellular carcinomahistone acetylationlenvatinib resistancem5C modification

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