TRIM8 is an E3 ubiquitin ligase that orchestrates innate immunity and cell survival through multiple signaling pathways. It promotes proteasomal degradation of the interferon-gamma repressor SOCS1 and activates NF-κB signaling by catalyzing Lys-63-linked polyubiquitination of TAK1, while negatively regulating TLR3/4-mediated responses through Lys-6- and Lys-33-linked polyubiquitination of TICAM1. TRIM8 also modulates STAT3 by degrading the inhibitor PIAS3. De novo truncating variants in TRIM8 cause a neuro-renal syndrome combining developmental delay, epilepsy, and focal segmental glomerulosclerosis (FSGS), with protein mislocalization from nuclear bodies to the diffuse nucleoplasm 1. Notably, variants closer to the C-terminus correlate with more prominent renal disease and fewer neurological manifestations 2. In non-alcoholic fatty liver disease, TRIM8 forms an E3 complex with TRIB3 that catalyzes K48-linked polyubiquitination of hepatic nuclear factor 4α, driving disease progression; disrupting this interaction via cell-penetrating peptides restores HNF4α and ameliorates hepatic steatosis 3. TRIM8 exhibits context-dependent oncogenic and tumor-suppressive roles. In Ewing sarcoma, TRIM8 degrades the EWS/FLI fusion oncoprotein and represents a selective dependency 4. In non-small cell lung cancer, TRIM8 acts as a tumor suppressor by targeting MYOF for K48-linked ubiquitination, reducing metastasis and correlating with improved overall survival 5. Conversely, in castration-resistant prostate cancer, reduced TRIM8 expression (via altered m6A methylation) stabilizes the EMT-promoting transcription factor NFIB, facilitating metastasis 6.