TRIM67 is a brain-enriched E3 ubiquitin ligase with multifaceted roles in cellular regulation and disease pathogenesis. Primary Function: TRIM67 functions as an E3 ubiquitin ligase involved in protein localization and degradation 1. In normal physiology, it plays essential roles in neuronal development, particularly in netrin-dependent axon guidance and morphogenesis through interaction with coronin 1A and the netrin receptor DCC 2. Mechanism: TRIM67 regulates protein stability through ubiquitin-mediated degradation. In colorectal cancer, TRIM67 stabilizes p53 by inhibiting MDM2-mediated p53 degradation, forming a self-amplifying TRIM67/p53 regulatory loop 1. In triple-negative breast cancer, TRIM67-mediated SMAD3 ubiquitination suppresses TGF-β signaling and EMT progression 3. In gliomas, TRIM67 overexpression alters cytoskeletal dynamics and promotes Rho GTPase/ROCK2-dependent membrane blebbing, increasing cell motility and tumor aggressiveness 4. Disease Relevance: TRIM67 exhibits context-dependent oncogenic or tumor-suppressive roles. It is downregulated in colorectal cancer but upregulated in oligodendrogliomas 14. Autoimmune TRIM67 autoantibodies associate with paraneoplastic cerebellar syndrome in 70% of cases with metastatic cancer 56. TRIM67 deficiency exacerbates hypothalamic inflammation and obesity-related metabolic dysfunction 7. Clinical Significance: TRIM67 reactivation may enhance chemotherapy responsiveness in colorectal cancer 1, while TRIM67 targeting could suppress glioma progression 4. Detection of anti-TRIM67 autoantibodies represents a high-risk paraneoplastic biomarker 5.