PSMD5 (proteasome 26S subunit, non-ATPase 5) functions as a critical chaperone and regulatory factor in 26S proteasome assembly. During initial assembly of the 19S regulatory particle base subcomplex, PSMD5 participates in an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module that subsequently dissociates following complex formation 1. Mechanistically, PSMD5 acts as a negative regulator of 26S and 30S proteasome assembly; PSMD5 loss increases holoenzyme levels and shifts proteasome composition toward more active forms, while PSMD5 elevation promotes disassembly of 30S proteasomes 2. PSMD5 also mediates TNF-α/NFκB-induced proteasome inhibition through enhanced interaction with PSMC2 in non-proteasome complexes 3. Disease relevance is significant across multiple conditions. In multiple myeloma, PSMD5 promoter hypermethylation occurs in 24% of proteasome inhibitor-refractory patients, reducing expression and promoting drug tolerance 1. In colorectal cancer, PSMD5 downregulation enhances 26S proteasome assembly, facilitating tumor adaptation to protein overload 4. Additionally, PSMD5 expression associates with methotrexate response prediction in rheumatoid arthritis 5 and juvenile idiopathic arthritis susceptibility 6. Clinically, PSMD5 modulation represents a potential therapeutic target for cancer and proteinopathy management.