TRIM33 is an E3 ubiquitin ligase that functions as a negative regulator of TGF-β/BMP signaling by monoubiquitinating SMAD4, which impairs its interaction with activated SMAD2/3 and prevents downstream transcriptional responses 1. Beyond SMAD regulation, TRIM33 mediates K48-linked polyubiquitination of p53, promoting its proteasomal degradation and enabling increased glycolysis in esophageal squamous cell carcinoma through upregulation of GLUT1, HK2, PKM2, and LDHA 2. In pulmonary fibrosis, TRIM33 serves as a protective factor; its overexpression in alveolar macrophages and fibroblasts suppresses TGF-β1-driven fibrotic responses, while TRIM33 deficiency worsens bleomycin-induced fibrosis 1. Similarly, reduced TRIM33 expression in endometriotic tissues associates with enhanced fibrosis through elevated TGF-β signaling and myofibroblast activation 3. TRIM33 also regulates O-GlcNAcylation homeostasis by controlling OGA protein stability through interaction with O-GlcNAcylated RBM14 4. In acute myeloid leukemia, TRIM33 acts as a tumor promoter through SETDB1 complex formation, suppressing NK cell-mediated immunosurveillance 5. These findings reveal TRIM33's multifaceted roles: anti-fibrotic in lung and endometrial contexts, pro-tumorigenic in some cancers, and immunomodulatory in leukemia.