Epigenomic Profiling Positions ATF7 as a Core Regulator of Colonic Inflammation

ABSTRACT Mitochondrial dysfunction plays a central role in epithelial damage and persistent inflammation in ulcerative colitis (UC), but the transcriptional mechanisms that govern mitochondrial quality control in the intestinal epithelium remain poorly defined. Here, we identify Activating Transcription Factor 7 (ATF7) as a key regulator of mitophagy in colonic epithelial cells. Integrative transcriptomic and epigenomic analyses of patient‐derived mucosal samples revealed marked ATF7 downregulation and widespread activation of inflammatory pathways. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that ATF7 directly binds to and activates the promoter of PINK1, a master regulator of mitophagy. Genetic ablation of ATF7 or PINK1 in human epithelial cells impaired mitophagy, disrupted mitochondrial membrane potential, and increased reactive oxygen species. In vivo, intestinal epithelial cell‐specific knockout of ATF7 or PINK1 exacerbated dextran sulfate sodium‐induced colitis, with greater epithelial injury, elevated cytokine production, and transcriptional activation of TNF, NF‐kappaB, and inflammatory bowel disease signalling pathways. These results establish ATF7 as a critical transcriptional regulator linking mitochondrial homeostasis to epithelial resilience in the inflamed colon.