Autoimmune diseases encompass over 80 distinct types, affecting approximately 7.6–9.4 % of the population globally. The intricate interplay between genetic predispositions and environmental triggers complicates early diagnosis and intervention. Abnormal macrophage differentiation and proliferation have been identified as key contributors to the pathogenesis of these conditions, though the precise molecular pathways remain poorly understood. Recent studies suggest that cereblon (CRBN), a target for immunomodulatory drugs like thalidomide, lenalidomide, and pomalidomide, may offer therapeutic potential for autoimmune diseases such as systemic lupus erythematosus. In this study, quantitative proteomics revealed that CRBN downregulated the calpain regulatory subunit, calpain small subunit 1 (CAPNS1), in macrophages. Subsequent biochemical assays demonstrated that CRBN modulated calpain activity, impacting autophagy processes during macrophage differentiation and microglial phagocytosis. Histological evaluation of CRBN-deficient mice indicated a marked increase in microglial populations in the brain. These findings highlight potential therapeutic targets and present new avenues for the treatment of autoimmune diseases.