Identification of COPZ1 as a Shared Candidate Ferroptosis-Related Hub Gene in Periodontitis and Inflammatory Bowel Disease

Abstract

Clinical and epidemiological evidence demonstrates a robust bidirectional link between inflammatory bowel disease (IBD) and periodontitis, with IBD patients having a significantly elevated risk of periodontitis. Although this association is well established, the shared molecular mechanisms remain unclear. Both IBD, including Crohn′s disease (CD) and ulcerative colitis (UC), and periodontitis feature aberrant ferroptosis activation, which drives oxidative damage and tissue breakdown. We therefore hypothesized that ferroptosis is a core pathogenic mechanism common to all three conditions. Using GEO transcriptomic data, we identified 116, 134, and 255 exploratory candidate ferroptosis-related differentially expressed genes in CD, UC, and periodontitis, respectively, with 55 candidate genes overlapping across all three conditions. Four machine learning–based feature selection algorithms consistently ranked COPZ1 as the top hub gene. In animal models of colitis and periodontitis, COPZ1 showed markedly elevated protein levels in inflamed intestinal and gingival tissues. In vitro experiments demonstrated that COPZ1 knockdown upregulated the expression of ferroptosis-inhibitory genes (Gpx4, Slc7a11, and Fth1) in RAW264.7-ASC macrophages under both basal and LPS-induced inflammatory conditions, and reversed LPS-mediated downregulation of Gpx4, suggesting that COPZ1 is involved in the regulation of ferroptosis in macrophages. Immune infiltration analysis revealed correlations between COPZ1 expression and the abundance of macrophages, neutrophils, B cell subsets, and T cell subsets, suggesting its association with differences in estimated immune cell composition. Single-cell RNA sequencing from CD patient biopsies further demonstrated heterogeneous COPZ1 expression across diverse intestinal immune cell types (including neutrophils, CD8⁺ T cells, CD4⁺ T cells, and macrophages) and linked to ferroptosis-associated intercellular signaling. In silico drug prediction identified nine small-molecule compounds that stably bound to COPZ1 through hydrogen bonds. Molecular dynamics simulations subsequently ranked BRD-K66453893 as the compound exhibiting the greatest structural stability among the tested candidates. Collectively, our findings identify COPZ1 as a shared candidate ferroptosis-related hub gene for CD, UC, and periodontitis, and highlight its association with the inflammatory immune microenvironment, thereby providing a promising therapeutic target for these interrelated chronic inflammatory disorders.