USP38 is a deubiquitinating enzyme that plays critical roles in cardiovascular disease pathogenesis through multiple mechanisms. In diabetic cardiomyopathy, USP38 is significantly upregulated and exacerbates cardiac dysfunction by deubiquitinating and inactivating ACAD11, leading to abnormal fatty acid oxidation and activation of the RAGE pathway 1. USP38 also promotes atrial fibrillation in diabetic mice by stabilizing iron regulatory protein 2 (IRP2), increasing intracellular iron overload and contributing to ferroptosis 2. In chr4 kidney disease, USP38 enhances ventricular arrhythmia susceptibility by stabilizing NOX4 through deubiquitination, resulting in increased oxidative stress and CaMKII hyperphosphorylation 3. Additionally, USP38 aggravates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing PTEN, thereby suppressing PI3K/Akt-mediated pro-survival signaling 4. Beyond cardiovascular disease, USP38 functions as an oncogene by stabilizing MDM2, leading to p53 degradation and enhanced cancer cell proliferation, migration, and invasion 5. Genome-wide association studies have identified USP38-DT as a novel susceptibility gene for multiple system atrophy 6. These findings establish USP38 as a crucial regulator of protein stability with significant therapeutic potential across multiple disease contexts.