Current landscape of the immunoproteasome: implications for disease and therapy

作者：Zifeng Zou, Yanglin Hao, Zetong Tao, Weicong Ye, Zilong Luo, Xiaohan Li, Ran Li, Kexiao Zheng, Jiahong Xia, Chao‐Yu Guo, Xi Zhang, Jie Wu · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02698-0 · 被引用次数：17 · 研究领域：Ubiquitin and proteasome pathways、Peptidase Inhibition and Analysis、interferon and immune responses

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.