Comparative transcriptomics may enable the discovery of cellular mechanisms of inflammatory diseases such as atherosclerosis and inflammatory bowel disease. By harnessing data from the healthy Human Cell Atlas and clinical patient samples, I will highlight recent findings on malignant inflammation orchestrated by immune cells across tissues and disease states. Along the gastrointestinal tract, I will show how analysis of harmonized single-cell RNA-seq can uncover epithelial cell metaplasia in inflammatory bowel disease, elucidating the role of altered stem cell dynamics in mucosal tissue architecture and inflammation progression. This comprehensive analysis provides data-driven insights into inflammatory mechanisms, highlighting the active contribution of both epithelial cells and fibroblasts. Further investigation into fibroblasts of Crohn’s disease reveals the epigenetic and transcriptomic rewiring of inflammation-associated fibroblast states, identifying the potential for reversibility with histone deacetylase (HDAC) inhibitors. This finding underscores the importance of epigenetic mechanisms in sustaining inflammatory responses, while opening new avenues for therapeutic interventions targeting the epigenetic memory of inflammatory cells.