TRIM6 is an E3 ubiquitin ligase that functions as a multifaceted regulator of cellular processes with significant pathological implications. Primary function: TRIM6 catalyzes K27-linked and K48-linked polyubiquitination of target proteins, leading to their proteasomal degradation or functional modification 1. Mechanism: TRIM6 mediates ubiquitination of diverse substrates including cGAS (triggering proteasomal degradation) 1, GPX3 (promoting oxidative stress) 2, SLC1A5 (inhibiting ferroptosis) 3, and DDX58/RIG-I (facilitating epithelial-mesenchymal transition) 4. Disease relevance: TRIM6 expression is significantly elevated in multiple cancers including gastric cancer, hepatocellular carcinoma, lung cancer, and gliomas, correlating with poor prognosis and reduced overall survival 543. In gastric cancer, TRIM6 suppresses antitumor immunity by degrading cGAS, contributing to immunotherapy resistance 1. TRIM6 upregulation in renal tubular epithelial cells promotes pyroptosis and inflammasome activation via GPX3 degradation 2. Clinical significance: TRIM6 expression serves as a predictive biomarker for treatment response in hepatitis B patients receiving interferon-alpha therapy 6 and represents a potential therapeutic target for overcoming immunotherapy resistance and enhancing chemosensitivity across multiple malignancies.