PSME1 encodes the α-subunit of the PA28 proteasome activator complex, which plays a crucial role in antigen processing and presentation. The protein functions as an activator of immunoproteasomes, specialized proteasome variants that generate peptides with hydrophobic C-termini suitable for MHC class I presentation 1. PSME1 associates with PSME2 to form the PA28α/β complex that enhances immunoproteasome activity and expands the diversity of MHC-I-bound peptides presented on cell surfaces 1. Mechanistically, PSME1 promotes the presentation of antigenic peptides by altering proteasomal cleavage patterns, with experimental evidence showing that compound-mediated enhancement of PSME1/PSME2 association can increase individual peptide presentation by >100-fold and unmask tumor neoantigens 1. The protein has significant clinical relevance across multiple diseases. In cancer, low pre-treatment PSME1 expression predicts favorable response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer patients 2, while it serves as a potential therapeutic target in multiple myeloma 1. PSME1 is also implicated in cardiovascular disease risk 3 and shows altered expression in rheumatoid arthritis, where it is significantly downregulated in CD4+ T-cell-derived exosomes 4. Additionally, PSME1 has been identified as a potential therapeutic target for Alzheimer's disease through Mendelian randomization analysis 5.