NINJ2 alleviates inflammatory bowel disease by regulating the macrophage ZBP1-PANoptosis pathway

Abstract Inflammatory bowel disease (IBD) is a chronic, relapsing intestinal disorder with a complex etiology and incompletely understood pathogenesis, posing significant challenges for clinical management. The NINJ2 gene is located on chromosome 12, a region enriched with IBD susceptibility loci, and is highly expressed in macrophages. However, its specific function and mechanistic role in IBD remain largely undefined. This study aimed to elucidate the function of the NINJ2 in IBD and delineate its underlying molecular mechanisms. By analyzing clinical samples and constructing a dextran sulfate sodium (DSS)-induced mouse model of IBD, we found that NINJ2 expression was significantly downregulated in the colon tissues of IBD patients and model mice. Systemic knockout of the Ninj2 gene ( Ninj2 −/ − ) resulted in markedly exacerbated colitis phenotypes. Utilizing macrophage depletion, adoptive transfer of bone marrow-derived macrophages (BMDMs), and IBD induction in mice with myeloid cell-specific knockout or overexpression of NINJ2, we established that macrophages are the pivotal effector cells mediating the intestinal protective effects of NINJ2. Mechanistically, NINJ2 deficiency was found to upregulate the expression of Z-DNA binding protein 1 (ZBP1) within macrophages. This upregulation subsequently triggered the activation of the PANoptosis pathway, and enhanced the production of pro-inflammatory cytokines, including IL-1β, IL-6, and IL-17. To our knowledge, this study provides the first evidence that NINJ2 confers protection against intestinal inflammation and helps maintain gut homeostasis by inhibiting the ZBP1-mediated PANoptosis pathway in macrophages. These findings offer novel insights into IBD pathogenesis and highlight NINJ2 as a potential therapeutic target for intervention.