USP40 is a deubiquitinating enzyme that functions as a critical regulator of protein stability across multiple cellular contexts. Primary function: USP40 removes K48-linked polyubiquitin chains from target proteins, thereby stabilizing their abundance and protecting cells from degradation 123. Mechanism: USP40 operates through tissue-specific and context-dependent pathways. In hepatocellular carcinoma (HCC), USP40 stabilizes Claudin-1 to promote proliferation and migration 1, and stabilizes YAP through a positive feedback loop that drives HCC progression 4. In acute myeloid leukemia, USP40 deubiquitinates c-MYC, preventing its proteasomal degradation and promoting cell proliferation while inhibiting apoptosis 3. Additionally, USP40 stabilizes CFLAR through interaction with adapter protein GMEB1, thereby inhibiting pro-caspase-8 activation and suppressing apoptosis in lung cancer 2. Disease relevance: USP40 promotes malignant progression in multiple cancers and is implicated in kidney disease pathology, where it maintains glomerular integrity through nestin regulation 5. In endothelial cells, USP40 protects against barrier disruption by deubiquitinating HSP90β 6. Clinical significance: High USP40 expression correlates with poor prognosis in HCC and AML 13, positioning USP40 as a promising therapeutic target for cancer treatment.