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TRIM21 as a Context-Dependent Regulator in Hepatocellular Carcinoma: Integrating Etiological Landscapes (HBV/NASH)

Jiatong Sun1, Zixuan Gao2, Yuanhao Li3

  • 1Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, People's Republic of China.

Journal of Hepatocellular Carcinoma
|March 20, 2026
PubMed

Insights

Tripartite motif-containing protein 21 (TRIM21) plays a dual role in hepatocellular carcinoma (HCC), influencing autophagy, drug resistance, metastasis, and oxidative stress. Understanding TRIM21

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocellular carcinoma (HCC) is a prevalent liver malignancy with poor prognosis.
  • Tripartite motif-containing protein 21 (TRIM21) is an E3 ubiquitin ligase involved in cellular processes.
  • TRIM21's role in HCC progression is complex and context-dependent.

Purpose of the Study:

  • To systematically review the mechanisms by which TRIM21 influences HCC progression.
  • To explore TRIM21's regulation of autophagy, drug resistance, metastasis, and oxidative stress in HCC.
  • To discuss TRIM21's significance in HBV- and NASH-associated HCC.

Main Methods:

  • Literature review of TRIM21's functions in hepatocellular carcinoma.
  • Analysis of TRIM21's involvement in key signaling pathways (e.g., autophagy, drug resistance, metastasis, ROS).
  • Examination of TRIM21's role in specific HCC etiologies (HBV, NASH).

Main Results:

  • TRIM21 modulates HCC autophagy through various pathways (e.g., CCR4-NOT, ATG14, RETREG1).
  • TRIM21 impacts drug resistance (oxaliplatin, sorafenib) via G6PD, MST1/YAP, and ApoE/cholesterol/PI3K-AKT cascades.
  • TRIM21 suppresses metastasis by ubiquitinating oncoproteins and regulates ROS balance via the SQSTM1/p62-Keap1-NRF2 axis.
  • TRIM21 is implicated in HBV and NASH-associated HCC pathogenesis.

Conclusions:

  • TRIM21 is a critical regulator of HCC progression through diverse mechanisms.
  • TRIM21's multifaceted roles suggest potential as a diagnostic marker and therapeutic target for HCC.
  • Further research into TRIM21's context-dependent functions is warranted for targeted HCC therapies.
Keywords:
HCCROSTRIM21autophagyclinical targetdrug resistancehepatocellular carcinomareactive oxygen species

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