Mechanisms and functions of the TRIM protein family in digestive system cancers

Tripartite motif-containing (TRIM) proteins are important RING-type E3 ubiquitin ligases that regulate protein fate and signal transduction through ubiquitin/ubiquitin-like modifications and non-ubiquitination mechanisms. In digestive system cancers, TRIM proteins exert highly context-dependent bidirectional effects. Here, we conceptualize TRIM proteins as signal integration nodes linking ubiquitin-mediated regulation, core signaling pathways, and adaptation to the tumor microenvironment.

This structured narrative review synthesizes English-language studies indexed in PubMed between January 2010 and October 2025. It focuses on the structural basis, multilevel regulation, molecular networks, phenotypic functions, prognostic relevance, and therapeutic implications of TRIM proteins in esophageal squamous cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma.

The modular architecture of TRIM proteins enables diverse substrate recognition and regulatory outputs. Cross-cancer analysis identifies pathway-convergent, phenotype-convergent, and pathway-phenotype bridging TRIM members that translate dysregulation of core pathways, including Wnt/β-catenin, PI3K/AKT, and p53, into proliferative, cell death-related, metastatic, metabolic, and immune phenotypes. Their functional direction is jointly shaped by tumor type, molecular subtype, substrate status, microenvironmental cues, and treatment context. Selected TRIM members show potential as prognostic biomarkers, risk-stratification indicators, and predictors of therapeutic response, whereas most TRIM-targeted strategies remain preclinical. Future studies should clarify ubiquitin-chain-specific regulatory logic, subtype-specific functions, and multilayered networks, while rigorously evaluating the specificity, safety, and clinical applicability of TRIM-directed combination therapies.