TRIM65 is an E3 ubiquitin ligase that regulates diverse cellular processes through protein ubiquitination and degradation mechanisms. The protein plays dual roles in innate immunity, both enhancing antiviral responses by promoting K63-linked ubiquitination of MDA5/IFIH1 during enteroviral infection 1 and strengthening type I interferon production through K6-linked ubiquitination of IRF3, which enhances its chr17 recruitment and IFNβ promoter binding 2. TRIM65 also negatively regulates inflammatory responses by promoting K48-linked ubiquitination and degradation of NLRP3 inflammasome components 3 and VCAM1 to limit LPS-induced lung inflammation 4. In pathological contexts, TRIM65 demonstrates complex disease-specific functions. It promotes renal fibrosis by degrading the cleavage factor NUDT21, leading to altered alternative polyadenylation of pro-fibrotic genes 5, while paradoxically protecting against diabetic kidney disease by suppressing ferroptosis through IREB2 degradation and inhibiting glycolysis 6. In cancer, TRIM65 acts as an oncogene, promoting hepatocellular carcinoma through NF2 degradation and YAP1 activation 7, and facilitating renal cell carcinoma progression by degrading the tumor suppressor BTG3 8. Additionally, TRIM65 contributes to atherosclerosis by promoting vascular smooth muscle cell phenotypic transformation via PI3K/Akt/mTOR pathway activation 9.