Abstract / Summary
Abstract Crohn's disease (CD) involves chronic mucosal inflammation and disrupted mitochondrial homeostasis, but genes linking myeloid inflammation to mitophagy remain incompletely defined. We integrated three training transcriptomic cohorts with two cross-cohort evaluation cohorts, protein-protein interaction analysis, machine learning, immune deconvolution, and single-cell RNA sequencing. Virtual knockout and preranked gene set enrichment analyses were used to examine S100A8-associated regulatory and mitochondrial programs. Twenty-four intersecting genes were identified, of which 18 formed a protein interaction network. A Lasso-gradient boosting machine model containing eight genes achieved areas under the curve of 0.995, 0.970, and 0.902 in the training set, GSE179285, and GSE20881, respectively. S100A8 was consistently differentially expressed across cohorts and was predominantly localized to myeloid cells. S100A8-positive myeloid cells showed transcription factor programs enriched in mitophagy and inflammatory signaling. Virtual S100A8 knockout predicted perturbations involving ADAMDEC1, SLC26A3, IL1RN, PLAUR, IL1B, SLC2A3, and SOD2, while continuous-expression analyses consistently linked S100A8 to oxidative stress, reactive oxygen species detoxification, intrinsic apoptosis, and mitochondrial cytochrome c release. These findings identify S100A8 as a candidate molecular link between myeloid inflammation and mitochondrial stress in CD.