Current landscape of the immunoproteasome: implications for disease and therapy

Abstract The immunoproteasome, an inflammation-induced proteasome variant, coordinates proteostasis and adaptive immunity by replacing constitutive subunits (β1, β2, β5) with inducible counterparts (β1i, β2i, β5i). This specialization enhances antigen processing for MHC class I presentation and oxidative protein clearance. Beyond immune regulation, it critically contributes to cardiovascular, respiratory, neurodegenerative, autoimmune, retinal, and oncological pathologies through mechanisms involving NF-κB activation, mitochondrial dysfunction, and inflammatory polarization. While β5i-specific inhibitors (e.g., ONX 0914) show therapeutic potential in preclinical models by mitigating proteotoxicity and inflammation, the immunoproteasome’s dual roles—cytoprotective or pathogenic—are context-dependent, necessitating precise targeting strategies. This review synthesizes recent advances in immunoproteasome biology, disease mechanisms, and therapeutic prospects, while highlighting unresolved questions on subunit specificity and microenvironmental regulation.