USP49 is a deubiquitinase that regulates multiple cellular processes through protein deubiquitination. As a histone H2B deubiquitinase, USP49 modulates transcriptional regulation by removing ubiquitin from histone H2B at lysine 120 1, controlling expression of genes involved in cell proliferation and the p53 pathway. USP49 suppresses PI3K/AKT signaling in non-small cell lung cancer by stabilizing PTEN through deubiquitination 2. The protein protects cardiomyocytes from ischemia-reperfusion injury by deubiquitinating and stabilizing DUSP1, which subsequently dephosphorylates JNK1/2 to prevent apoptosis 3. However, USP49 exhibits context-dependent oncogenic roles. In esophageal adenocarcinoma, USP49 promotes ferroptosis resistance by stabilizing SHCBP1, enhancing β-catenin-mediated GPX4 expression 4. In colorectal cancer, USP49 is transcriptionally activated by c-MYC and stabilizes BAG2 to promote chemoresistance 5. In esophageal squamous cell carcinoma, USP49 undergoes liquid-liquid phase separation and stabilizes RPA70 to promote DNA homologous recombination repair and radioresistance 6. USP49 can also stabilize APOBEC3G to enhance anti-HIV-1 activity, and negatively regulates antiviral responses via STING1 deubiquitination. Notably, USP49 is regulated by Fbxo45-mediated ubiquitination and degradation in pancreatic cancer 7.