TRIB3 is an inactive pseudokinase that serves as a critical regulator of cellular stress responses and metabolic homeostasis. The protein functions primarily as a scaffold protein that modulates multiple signaling pathways through direct protein-protein interactions. TRIB3 acts as a negative feedback regulator in the integrated stress response by interacting with transcription factors ATF4 and DDIT3/CHOP to inhibit their transcriptional activity 1. The protein disrupts insulin signaling by directly binding to AKT kinases and blocking their activation, while also interacting with NF-κB p65 to inhibit its transcriptional activity 1. TRIB3 demonstrates significant pathological relevance across multiple disease contexts. In liver disease, TRIB3 forms a complex with TRIM8 to mediate HNF4α degradation through K48-linked ubiquitination, contributing to NAFLD progression 2. The protein promotes hepatic fibrosis by interacting with autophagy receptor SQSTM1, disrupting autophagic flux and enhancing pro-fibrotic exosome secretion 3. In cancer, TRIB3 inhibits CD8+ T cell infiltration by suppressing STAT1-mediated CXCL10 transcription, creating an immunologically 'cold' tumor environment 4. Additionally, TRIB3 promotes vascular calcification in chr20 kidney disease by facilitating Smurf1 self-ubiquitination and stabilizing osteogenic transcription factors RUNX2 and SMAD1 5. These findings establish TRIB3 as a potential therapeutic target for metabolic diseases, fibrosis, and cancer immunotherapy.