Therapeutic Potential of AIM2 in Rheumatoid Arthritis: Evidence from Multi-Omics and Preclinical Models

Objective Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. This study aimed to elucidate the pathogenic role of the cytosolic DNA sensor AIM2 in RA, focusing on its expression patterns, functional mechanisms in synovial fibroblasts (FLS) and macrophages, and therapeutic potential in preclinical models. Methods Multi-omics analyses were performed on synovial tissues from RA and osteoarthritis (OA) patients (n = 24), integrating bulk RNA-seq, single-cell RNA-seq (scRNA-seq), and public datasets (GEO, PEAC). Functional assays included AIM2 overexpression/knockdown in RA fibroblast-like synoviocytes (FLS) and THP-1-derived macrophages, assessing proliferation, migration, and inflammatory responses. Collagen-induced arthritis (CIA) mice were treated with AIM2-targeting AAV9 to evaluate therapeutic effects. Results AIM2 was significantly upregulated in RA synovium versus OA/healthy controls ( P  < 0.05) and positively correlated with disease activity ( P  < 0.05). scRNA-seq localized AIM2 overexpression primarily to FLS and macrophages. In vitro , AIM2 promoted FLS migration/proliferation and upregulated pro-inflammatory genes ( IL6 , CXCL1 , TNFSF18 ), while suppressing adhesion genes. In M1 macrophages, AIM2 overexpression activated NF-κB/TNF pathways and enhanced IL6 , MMP3 , and MMP12 expression. CIA mice with AIM2 knockdown showed reduced arthritis scores (vs. controls, P  < 0.05), attenuated joint destruction on histology/micro-CT, and downregulated synovial inflammatory ( Il1r1 , Il20ra ) and bone-degrading ( Mmp13 , Mmp14 ) genes. Conclusion AIM2 drives RA pathogenesis by enhancing FLS invasiveness, promoting pro-inflammatory M1 macrophage polarization, and activating key destructive pathways. Targeted AIM2 knockdown alleviates arthritis severity in vivo , supporting its potential as a novel therapeutic target for RA.