CBLL1 (Cbl proto-oncogene like 1) is a multifunctional E3 ubiquitin ligase with both canonical and emerging non-canonical roles in cellular regulation. As an E3 ubiquitin ligase, CBLL1 mediates ubiquitination and degradation of E-cadherin, promoting epithelial-to-mesenchymal transition and facilitating endocytosis 1. This E-cadherin targeting mechanism drives cancer progression across multiple malignancies 23. Beyond its ubiquitin ligase function, CBLL1 serves as a component of the WMM m6A methyltransferase complex, contributing to N6-methyladenosine modification of RNAs with roles in mRNA splicing and processing 45. Clinically, CBLL1 demonstrates cancer-type-specific expression patterns with prognostic significance. In colorectal cancer, high CBLL1 expression specifically marks the CMS2 subtype and associates with worse overall survival 2. In non-small cell lung cancer, CBLL1 upregulation correlates with tumor size and promotes G1/S cell cycle progression 3. Conversely, elevated CBLL1 in endometrial tissue promotes stromal cell senescence via PTEN inhibition, contributing to recurrent spontaneous abortion pathogenesis 6. These distinct roles highlight CBLL1's context-dependent functionality and its potential as a tissue-specific therapeutic target and biomarker for precision medicine applications 5.