TRIM21 as a Context-Dependent Regulator in Hepatocellular Carcinoma: Integrating Etiological Landscapes (HBV/NASH) with Core Tumor Progression Mechanisms

Jiatong Sun,1 Zixuan Gao,2 Yuanhao Li,3 Jiajun Gao,1 Peiyin Wang,1 Yibo Qin,1 Yanru Chen,4 Ruihong Zhang1 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; 2Clinical Medicine (5+3 Integrated Bachelor-Master Program), Hebei Medical University, Shijiazhuang, People’s Republic of China; 3School of Stomatology, Qingdao University, Qingdao, People’s Republic of China; 4Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Yanru Chen, Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China, Email 1206142926@qq.com Ruihong Zhang, Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, People’s Republic of China, Email Rrui1216@163.comAbstract: Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress response. Accumulating evidence highlights its context-dependent regulatory roles in hepatocellular carcinoma (HCC)—the most prevalent primary liver malignancy with high mortality and limited therapeutic efficacy. This review systematically summarizes the core mechanisms by which TRIM21 orchestrates HCC progression: ① Autophagy regulation: TRIM21 modulates HCC autophagy via multiple axes, including CCR4-NOT complex (TNKS1BP1/CNOT4)-mediated substrate ubiquitination, ATG14-dependent autophagosome initiation, and RETREG1-driven reticulophagy, with context-dependent effects on tumor proliferation. ② Drug resistance: TRIM21 enhances oxaliplatin sensitivity by ubiquitinating and degrading G6PD (the rate-limiting enzyme of the pentose phosphate pathway), while its role in sorafenib resistance involves dual pathways—the MST1/YAP axis and the ApoE/cholesterol/PI3K-AKT cascade. ③ Metastasis suppression: TRIM21 restricts HCC invasion and metastasis by ubiquitinating key oncoproteins, preserving epithelial integrity and inhibiting mesenchymal transition. ④ Reactive oxygen species (ROS) balance: TRIM21 regulates oxidative stress in HCC via the SQSTM1/p62-Keap1-NRF2 axis, coordinating with HIF1α to modulate antioxidant responses and tumor cell survival. Additionally, we discuss the regulatory significance of TRIM21 in HCC associated with hepatitis B virus (HBV) infection (via HBx/DNA polymerase ubiquitination) and nonalcoholic steatohepatitis (NASH) (via suppressing lipogenic enzymes to reduce steatosis-driven carcinogenesis). This review provides a theoretical basis for TRIM21 as a potential diagnostic marker and therapeutic target for HCC. Keywords: TRIM21, hepatocellular carcinoma, HCC, autophagy, drug resistance, reactive oxygen species, ROS, clinical target