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USP33 contributes to EMT and Lenvatinib resistance by enhancing eEF1A1-mediated ILEI protein synthesis in

Hongcheng Lu1, Guohui Hu2, ZhiHao Huang1

  • 1Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.

International Journal of Biological Macromolecules
|May 17, 2026
PubMed

Insights

Ubiquitin-specific protease 33 (USP33) drives lenvatinib resistance in advanced liver cancer by promoting epithelial-mesenchymal transition (EMT). Targeting the USP33/eEF1A1/ILEI pathway may overcome treatment failure in hepatocellular carcinoma (HCC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lenvatinib resistance is a major cause of treatment failure in advanced hepatocellular carcinoma (HCC).
  • The molecular mechanisms underlying lenvatinib resistance in HCC are not fully understood.

Purpose of the Study:

  • To identify key molecular factors contributing to lenvatinib resistance in HCC.
  • To elucidate the role of ubiquitin-specific protease 33 (USP33) in lenvatinib resistance and epithelial-mesenchymal transition (EMT).

Main Methods:

  • CRISPR knockout library screening targeting human ubiquitination-related proteins.
  • Transcriptome sequencing to analyze USP33-induced gene expression changes.
  • Proteomic analysis to identify downstream targets of USP33.
  • Deubiquitination assays to investigate USP33's enzymatic activity on eEF1A1.

Main Results:

  • USP33 was identified as a critical factor in lenvatinib resistance in HCC.
  • USP33 promotes EMT and lenvatinib resistance; its downregulation suppresses EMT and enhances sensitivity.
  • USP33 deubiquitinates eukaryotic translation elongation factor 1A1 (eEF1A1), stabilizing it and promoting interleukin-like EMT-inducing factor (ILEI) synthesis.
  • The USP33/eEF1A1/ILEI axis was identified as a key regulator of EMT and lenvatinib resistance.

Conclusions:

  • The USP33/eEF1A1/ILEI axis plays a significant role in promoting EMT and lenvatinib resistance in HCC.
  • USP33 is a potential therapeutic target for overcoming lenvatinib resistance in hepatocellular carcinoma.
  • These findings provide a rationale for developing strategies to enhance lenvatinib efficacy in HCC patients.
Keywords:
EMTHepatocellular carcinomaILEILenvatinibUSP33eEF1A1

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