TRIP12 is an E3 ubiquitin ligase that plays critical roles in protein degradation, DNA repair, and cellular signaling pathways 1. As part of the HECT family of ubiquitin ligases, TRIP12 specifically assembles K29-linked ubiquitin chains and facilitates K29/K48-branched chain formation, which accelerates proteasomal degradation of target proteins 23. The protein regulates multiple cellular processes through substrate-specific ubiquitination, including DNA damage response by suppressing RNF168 spreading at damaged chr2, and cell cycle control through degradation of p19ARF 1. TRIP12 also modulates Wnt signaling by ubiquitinating BRG1 to promote its interaction with β-catenin for target gene activation 4. In disease contexts, TRIP12 contributes to Parkinson's disease pathogenesis by ubiquitinating glucocerebrosidase, leading to α-synuclein accumulation and neurodegeneration 5. TRIP12 regulates intestinal permeability in metabolic dysfunction-associated steatohepatitis through TFEB ubiquitination and autophagy inhibition 6. Clinically, TRIP12 haploinsufficiency causes Clark-Baraitser syndrome, characterized by intellectual disability, autism spectrum disorder, and distinctive facial features 7. TRIP12 also enhances the efficacy of targeted protein degradation therapies like PROTACs and supports CD8+ T cell activation through PD-1 regulation 28.