PSMB6 encodes the beta 6 subunit of the 20S proteasome core complex, which exhibits peptidylglutamyl-hydrolizing (caspase-like) activity essential for protein degradation 1. This subunit plays a critical structural role in proteasome assembly, as PSMB6 knockout is lethal to multiple myeloma cells and prevents proper splicing of other catalytic subunits (PSMB5, PSMB7, PSMB8, PSMB10), with its structural contribution being more important than catalytic activity 2. PSMB6 is widely expressed across tissues, with highest expression in spleen, and participates in MHC class I antigen presentation 3. The gene demonstrates significant clinical relevance in cancer, where elevated PSMB6 expression correlates with poor prognosis in lung adenocarcinoma and promotes tumor cell proliferation, migration, and invasion 4. In multiple myeloma, PSMB6 upregulation contributes to bortezomib resistance, while its inhibition by STAT3 inhibitors can overcome this resistance 5. PSMB6 also regulates cellular metabolism by modulating the Akt/SREBP1 pathway to influence fatty acid synthesis and ATP production 6. Genetic polymorphisms in PSMB6 are associated with immune traits and treatment response, making it a potential biomarker for personalized therapy 7.