PSMD4 (proteasome 26S subunit ubiquitin receptor, non-ATPase 4) is a ubiquitin receptor subunit of the 26S proteasome complex that selects polyubiquitinated proteins for ATP-dependent degradation through its ubiquitin-interacting motifs 1. This component maintains protein homeostasis by removing misfolded, damaged, or unnecessary proteins, thereby regulating cell cycle progression, apoptosis, and DNA damage repair. PSMD4 functions as a critical regulatory node in both normal and pathological contexts. During DNA damage responses, PSMD4/Rpn10 undergoes ATM/ATR/DNA-PK-mediated phosphorylation at Ser266, which reduces substrate binding affinity and spares essential DNA repair proteins like BRCA1 from premature degradation 2. Additionally, PSMD4 mediates stress-induced degradation of regulatory proteins like TXNL1 upon oxidative stress exposure 3. Clinically, PSMD4 is significantly upregulated in multiple malignancies. In hepatocellular carcinoma, elevated PSMD4 promotes tumor growth via Akt/COX2 pathway activation and p53 inhibition 4. In multiple myeloma, PSMD4 expression inversely correlates with overall survival, and its inhibition triggers polyubiquitinated protein accumulation, cell cycle arrest, and apoptosis 5. PSMD4 knockout reduces colibactin-induced cell cycle arrest, suggesting roles in cancer initiation 6. Hypoxia upregulates PSMD4 expression via HIF-1α in prostate cancer cells 7. PSMD4 represents a therapeutic target for enhancing immunotherapy responses and overcoming proteasome inhibitor resistance.