Ubiquitin-proteasome system (UPS) is the primary non-lysosomal pathway of protein degradation in eukaryotic cells, whose proteolytic activities are closely associated with subunits β1, β2, β5. Subunits β1, β2, β5 can be replaced respectively by subunits β1i, β2i and low-molecular-mass proteasome 7 (LMP7 or β5i), with β5i being most active and the new structure being called immunoproteasome. β5i plays an important role in autoimmune diseases, cardiovascular and cerebrovascular diseases, obesity and metabolic diseases, and tumor. This article introduced the latest progress in β5i in relation to the above diseases in view of providing effective intervention targets for drug therapy and improving the prognosis of the diseases.