PSMB4 encodes a non-catalytic beta subunit of the 20S proteasome core complex, essential for protein degradation pathways. As part of the 26S proteasome (when associated with 19S regulatory particles), PSMB4 participates in ATP-dependent degradation of ubiquitinated proteins, crucial for maintaining protein homeostasis 1. The protein also functions in ubiquitin-independent degradation when the 20S proteasome associates with PA200 or PA28 regulators, supporting processes like spermatogenesis and MHC class I antigen presentation. PSMB4 demonstrates significant clinical relevance across multiple diseases. In cancer, elevated PSMB4 expression correlates with poor prognosis in glioblastoma, where its knockdown reduces tumor cell proliferation, migration, and invasion while enhancing temozolomide efficacy 1. The protein is upregulated in pulmonary neuroendocrine tumors and associated with proliferative activity 2. PSMB4 also serves as a potential biomarker for pancreatic cancer when detected in circulating extracellular vesicles 3. In psychiatric disorders, PSMB4 shows causal associations with depression risk and represents a shared comorbidity locus for depression and schizophrenia 45. Additionally, PSMB4 appears to influence aging processes and may serve as a therapeutic target for age-related conditions 6.