USP21 is a deubiquitinating enzyme (DUB) that removes ubiquitin from target proteins, with multifaceted roles in epigenetic regulation and disease pathogenesis. Primary function: USP21 deubiquitinates histone H2A to relieve transcriptional repression and regulate gene expression 1. Mechanism: USP21 removes K48-linked ubiquitin chains from diverse substrates including HSP90, ENO1, YBX1, G3BP1, and MOF, stabilizing these proteins to promote downstream signaling 2345. In vascular smooth muscle cells, USP21 stabilizes ALDH2 to promote phenotypic changes 6. USP21 also antagonizes ribosome quality control by deubiquitinating 40S ribosomal proteins. Disease relevance: USP21 is upregulated in multiple cancers including cholangiocarcinoma, esophageal squamous cell carcinoma, and prostate cancer, where it promotes aerobic glycolysis, proliferation, and metastasis 234. USP21 exacerbates abdominal aortic aneurysm progression 6, and promotes hyperglycemia in metabolic disorders 7. In breast cancer, USP21 interaction with BRCA2 regulates homologous recombination repair 8. Clinical significance: USP21 inhibition via disulfiram or the selective inhibitor Bay-805 demonstrates therapeutic potential across multiple cancer types 2345, positioning USP21 as an emerging drug target.