Background <p>Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer and continues to be a major cause of cancer-related death globally. The identification of novel molecular targets is essential for developing effective therapeutic strategies.</p> Methods <p>In this study, we investigated the functional and mechanistic role of the E3 ubiquitin-protein ligase CBL in NSCLC progression. CBL expression was analyzed in NSCLC tumor tissues and cell lines using quantitative RT-PCR and Western blotting. The impact of CBL on NSCLC cell proliferation, migration, and invasion was assessed by a number of in vitro functional tests. Co-immunoprecipitation (Co-IP) and ubiquitination assays were performed to elucidate the molecular interaction between CBL and kinase insert domain receptor (KDR), a key mediator of angiogenesis.</p> Results <p>CBL expression was markedly reduced in NSCLC tissues and cell lines relative to normal equivalents. Gain- and loss-of-function tests demonstrated that CBL suppressed the NSCLC cell proliferation, migration, and invasion, highlighting its tumor-suppressive role. Mechanistically, CBL regulates KDR protein degradation via ubiquitination, thereby disrupting KDR-mediated signaling pathways associated with angiogenesis and tumor progression. Notably, overexpression of KDR reversed the anti-tumor effects of CBL, restoring the aggressive phenotype of NSCLC cells. These results suggest that CBL acts as a negative regulator of NSCLC malignancy through targeted degradation of KDR.</p> Conclusion <p>Our findings identify CBL as a functional tumor suppressor in NSCLC that exerts its anti-cancer effects via ubiquitin-mediated degradation of KDR. The CBL-KDR axis signifies a new regulatory route with significant therapeutic potential for NSCLC therapy.</p>