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ACSS2 drives Lenvatinib resistance in hepatocellular carcinoma through palmitoylation

Hao Xu1, Hao Wang1, Shi-Zhe Yu1

  • 1Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China; Cancer Metastasis Institute, Fudan University, Shanghai, China.

Pharmacological Research
|May 14, 2026
PubMed

Insights

Acquired resistance to Lenvatinib in advanced hepatocellular carcinoma (HCC) is driven by ACSS2-mediated metabolic changes. Targeting ACSS2 with inhibitors can overcome this resistance, offering a new therapeutic strategy for HCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Lenvatinib is a key treatment for advanced hepatocellular carcinoma (HCC).
  • Acquired drug resistance limits Lenvatinib's clinical efficacy.
  • Metabolic reprogramming is linked to therapeutic resistance, but mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of metabolic reprogramming in Lenvatinib resistance in HCC.
  • To identify specific molecular mechanisms driving resistance to Lenvatinib.
  • To explore ACSS2 as a therapeutic target to overcome Lenvatinib resistance.

Main Methods:

  • Transcriptomic and metabolomic profiling of Lenvatinib-resistant HCC cells.
  • Genetic manipulation of ACSS2 expression (knockdown and overexpression).
  • Assessment of EGFR palmitoylation and degradation.
  • In vivo studies using subcutaneous and hydrodynamic transfection HCC models.

Main Results:

  • ACSS2 expression was significantly associated with Lenvatinib resistance.
  • ACSS2 knockdown restored sensitivity, while overexpression conferred resistance.
  • ACSS2 promotes palmitate biosynthesis, stabilizing EGFR and sustaining signaling.
  • Inhibition of ACSS2 synergized with Lenvatinib to overcome resistance in vivo.

Conclusions:

  • ACSS2-mediated metabolic-epigenetic crosstalk is a critical driver of Lenvatinib resistance in HCC.
  • The ACSS2/EGFR axis represents a metabolic vulnerability in resistant HCC.
  • Targeting ACSS2 is a promising strategy to reverse Lenvatinib resistance in advanced HCC.
Keywords:
Hepatocellular carcinomaLenvatinib resistancePalmitoylationTumor metabolism

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