PSMA2 is a structural component of the 20S proteasome core complex that catalyzes ATP-dependent degradation of ubiquitinated proteins when associated with 19S regulatory particles (forming the 26S proteasome), as well as ubiquitin-independent proteolysis when bound to PA200 or PA28 regulatory complexes. This proteolytic function is essential for protein homeostasis, spermatogenesis, and generation of MHC class I-presented antigenic peptides. PSMA2 expression is dysregulated across multiple human cancers and disease contexts. Elevated PSMA2 levels correlate with poor prognosis in gliomas and acute myeloid leukemia (AML), where it promotes epithelial-mesenchymal transition and tumor progression 1. In AML, PSMA2 was identified as part of a 13-gene exosome-based prognostic signature predicting 3-year survival with 83.2% accuracy 2. PSMA2 dysfunction also impairs antiviral immunity; influenza A virus and Zika virus exploit PSMA2 to suppress host oxidative stress responses and restrict viral clearance, making it a critical host factor for viral maturation 34. In ulcerative colitis, PSMA2 levels are elevated in salivary exosomes and associated with pro-inflammatory macrophage activation 5. Proteasome inhibitors—including bortezomib, carfilzomib, and ixazomib—target PSMA2-containing complexes and are established therapies for multiple myeloma and select lymphomas.