USP28 is a deubiquitinase that serves multifaceted roles in cellular homeostasis and disease regulation. Primary Function: USP28 functions as a cysteine-type deubiquitinase involved in protein stability regulation through targeted deubiquitination of key substrates across diverse pathways. Mechanism: USP28 deubiquitinates and stabilizes multiple proteins including MYC, CLSPN, PPARα, TRIM21, MAST1, and SOX9, preventing their proteasomal degradation. In DNA damage response, USP28 forms p53BP1-USP28-p53 complexes transmitted to daughter cells, monitoring mitotic duration and preventing proliferation of genomically unstable progeny 1. USP28 stabilizes PPARα to promote Mfn2 transcription, maintaining mitochondrial homeostasis 2, and stabilizes SOX9 to enhance DNA damage repair gene expression 3. Disease Relevance: USP28 dysregulation promotes multiple pathologies. Elevated USP28 drives cardiac hypertrophy via TRIM21 stabilization and oxidative stress 4, cisplatin resistance through MAST1 stabilization 5, PARP inhibitor resistance in ovarian cancer via SOX9 stabilization 3, and breast cancer stem-like properties through MYC stabilization 6. Conversely, USP28 reduction protects against diabetic cardiomyopathy 2. Clinical Significance: USP28 represents a potential therapeutic target; selective inhibitors show promise in sensitizing resistant cancers to conventional therapies and ameliorating metabolic cardiomyopathy.