Abstract Background Mitochondrial dysfunction plays a central role in epithelial damage and persistent inflammation in ulcerative colitis (UC), yet the transcriptional mechanisms governing mitochondrial quality control in intestinal epithelium remain poorly defined. Methods Colonic mucosal samples from patients and controls were collected for gene expression and binding site analysis via ChIP-seq and RNA-seq. Intestinal epithelial cell-specific knockout mouse models were established to induce DSS-induced colitis. Cell culture, CRISPR editing, and flow cytometry were used to verify ATF7’s regulation of PINK1 and mitochondrial function. ELISA, Western blot, and qPCR were employed for quantitative analysis of relevant indicators. Results This study identified 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, accompanied by more severe epithelial injury, elevated cytokine production, and transcriptional activation of TNF, NF-κB, and inflammatory bowel disease signaling pathways. Conclusion This study concludes that activating transcription factor 7 (ATF7) acts as a critical transcriptional regulator in ulcerative colitis (UC). ATF7 is significantly downregulated in the colonic mucosa of active UC patients, associated with activated inflammatory pathways. Mechanistically, ATF7 directly binds to and activates the promoter of PINK1, a key mitophagy regulator. Genetic ablation of ATF7 or PINK1 impairs mitophagy, disrupts mitochondrial membrane potential, and increases reactive oxygen species in human colonic epithelial cells. In vivo, intestinal epithelial cell-specific knockout of ATF7 or PINK1 exacerbates DSS-induced colitis, causing more severe epithelial damage, elevated pro-inflammatory cytokines, and enhanced activation of TNF, NF-κB, and IBD-related signaling. These findings identify ATF7 as a pivotal mediator safeguarding intestinal epithelial integrity via PINK1-dependent mitophagy, highlighting its potential as a therapeutic target for UC References: 1 I. P. Salt, J. R. C. Nunes, and M. D. Fullerton, “Metformin Again? Atheroprotection Mediated by Macrophage AMPK and ATF1,” Cardiovascular Research 117 (2021): 1233–1234. 2 R. Shi, J. Wang, Z. Zhang, et al., “ASGR1 Promotes Liver Injury in Sepsis by Modulating Monocyte-To-Macrophage Differentiation via NF-κB/ATF5 Pathway,” Life Sciences 315, no. 121 (2023): 339. 3 M. Chen, Y. Liu, Y. Yang, et al., “Emerging Roles of Activating Transcription Factor (ATF) Family Members in Tumourigenesis and Immunity: Implications in Cancer Immunotherapy,” Genes & Diseases 9 (2022): 981–999. 4 Y. Chen and G. W. Dorn, “PINK1-Phosphorylated Mitofusin 2 Is a Parkin Receptor for Culling Damaged Mitochondria,” Science 340 (2013): 471–475. Conflict of interest: Ms. Liu, Fang: No conflict of interest
F Liu (Thu,) studied this question.