TRIM38, a member of the tripartite motif (TRIM)-containing protein family, functions as a ubiquitin E3 protein ligase. It is involved in diverse intracellular physiological processes, such as cell proliferation, differentiation, apoptosis, and antiviral defense, and plays a significant role in innate immune and inflammatory responses [4]. It participates in various signaling pathways including TRAF6/TAK1/NF-κB, MYC, and RIG-I-related pathways [1,2,3]. Genetic models like gene knockout (KO) can be valuable for studying its functions.

In a rat cardiomyoblast cell line (H9c2), TRIM38 reduction activated the TAK1/NF-κB signaling pathway, attenuating the anti-apoptotic capacity and anti-inflammatory potential during hypoxia/reoxygenation injury [1]. In colorectal cancer, DNA hypermethylation downregulated TRIM38, which was correlated with poor prognosis. TRIM38 functioned as a tumor suppressor by enhancing CCT6A ubiquitination to inhibit the MYC pathway [2]. In respiratory syncytial virus-infected cells, TRIM38 downregulated type I interferon expression by competing with TRIM25 to bind RIG-I [3]. In chondrocytes, decreased TRIM38 levels after IL-1β stimulation led to increased apoptosis and degeneration, while overexpression alleviated these effects via suppressing NF-κB signaling [5]. In osteoclast and osteoblast differentiation, TRIM38 overexpression in precursor cells affected differentiation and function by regulating NF-κB activation through TAB2 degradation [6]. In bladder cancer, low TRIM38 expression was associated with advanced clinical characteristics, and TRIM38 restricted tumor progression by promoting GLUT1 ubiquitination and degradation [7]. In NAFLD, TRIM38 expression was downregulated, and its depletion aggravated hepatic steatosis, inflammation, and fibrosis by promoting TAB2 degradation and suppressing MAPK signaling [8].

In conclusion, TRIM38 plays essential roles in multiple biological processes and diseases. Through model-based research, especially KO studies, it has been revealed that TRIM38 is involved in inflammation, apoptosis, tumor progression, and metabolic diseases. Understanding TRIM38 functions contributes to uncovering disease mechanisms and may provide potential therapeutic targets for conditions such as myocardial ischemia/reperfusion injury, colorectal cancer, osteoarthritis, and NAFLD.

References:

1. Lu, Zhengri, Deng, Mengen, Ma, Genshan, Chen, Lijuan. 2022. TRIM38 protects H9c2 cells from hypoxia/reoxygenation injury via the TRAF6/TAK1/NF-κB signalling pathway. In PeerJ, 10, e13815. doi:10.7717/peerj.13815. https://pubmed.ncbi.nlm.nih.gov/36061751/

2. Zhang, Yue, Tan, Xinyu, Wang, Lu, Feng, Yifei, Sun, Yueming. 2025. TRIM38 Suppresses the Progression of Colorectal Cancer via Enhancing CCT6A Ubiquitination to Inhibit the MYC Pathway. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12, e2411285. doi:10.1002/advs.202411285. https://pubmed.ncbi.nlm.nih.gov/40047371/

3. Sun, Qingqing, Han, Xiao, Meng, Lingtong, Wei, Lin, Ma, Cuiqing. 2024. TRIM38 Induced in Respiratory Syncytial Virus-infected Cells Downregulates Type I Interferon Expression by Competing with TRIM25 to Bind RIG-I. In Inflammation, 47, 1328-1343. doi:10.1007/s10753-024-01979-7. https://pubmed.ncbi.nlm.nih.gov/38630167/

4. Hu, Ming-Ming, Shu, Hong-Bing. 2017. Multifaceted roles of TRIM38 in innate immune and inflammatory responses. In Cellular & molecular immunology, 14, 331-338. doi:10.1038/cmi.2016.66. https://pubmed.ncbi.nlm.nih.gov/28194022/

5. Hu, Shouye, Li, Yanqi, Wang, Bo, Peng, Kan. 2021. TRIM38 protects chondrocytes from IL-1β-induced apoptosis and degeneration via negatively modulating nuclear factor (NF)-κB signaling. In International immunopharmacology, 99, 108048. doi:10.1016/j.intimp.2021.108048. https://pubmed.ncbi.nlm.nih.gov/34426118/

6. Kim, Kabsun, Kim, Jung Ha, Kim, Inyoung, Seong, Semun, Kim, Nacksung. 2018. TRIM38 regulates NF-κB activation through TAB2 degradation in osteoclast and osteoblast differentiation. In Bone, 113, 17-28. doi:10.1016/j.bone.2018.05.009. https://pubmed.ncbi.nlm.nih.gov/29753717/

7. Wang, Xiaojing, He, Hongchao, Rui, Wenbin, Zhu, Yu, Xie, Xin. 2021. TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer. In Journal of translational medicine, 19, 508. doi:10.1186/s12967-021-03173-x. https://pubmed.ncbi.nlm.nih.gov/34906161/

8. Yao, Xinxin, Dong, Ruixiang, Hu, Sha, Li, Hongliang, Zhang, Peng. 2023. Tripartite motif 38 alleviates the pathological process of NAFLD-NASH by promoting TAB2 degradation. In Journal of lipid research, 64, 100382. doi:10.1016/j.jlr.2023.100382. https://pubmed.ncbi.nlm.nih.gov/37116711/