USP14 is a proteasome-associated deubiquitinase that removes ubiquitin from proteasome-targeted proteins, ensuring ubiquitin regeneration at the proteasome 1. As a reversibly associated proteasomal subunit, USP14 exists in both proteasome-bound and free cellular forms 2. Beyond proteasomal protein degradation, USP14 plays diverse regulatory roles: it is required for CXCR4 chemokine receptor degradation critical for cell chemotaxis 3, serves as a physiological inhibitor of ER-associated degradation 4, and stabilizes the viral DNA sensor cGAS to enhance innate immune defense 5. USP14 inhibits OPTN-mediated autophagic degradation of KDM4D, thereby negatively regulating histone methylation marks 1. Clinically, USP14 dysregulation contributes to multiple diseases. In hepatocellular carcinoma, USP14-mediated TUBA1A K370 deubiquitination promotes tumorigenesis through AKT activation, with targeting this axis blocking liver cancer in vivo 6. USP14 overexpression exacerbates nonalcoholic fatty liver disease progression via HSP90AA1-stabilization-dependent CYP2E1 accumulation 7. In atherosclerosis, USP14-mediated cGAS stabilization promotes pro-inflammatory macrophage polarization 8. Conversely, USP14 inhibition promotes DNA damage repair and suppresses granulosa cell senescence in premature ovarian insufficiency 9. These findings position USP14 as a promising therapeutic target across multiple pathologies.