2. Academic Validation
  3. c-Myc-PANK3-EMT axis regulates the structure and function of intestinal barrier in ulcerative colitis

c-Myc-PANK3-EMT axis regulates the structure and function of intestinal barrier in ulcerative colitis

  • J Adv Res. 2025 Dec 8:S2090-1232(25)00996-8. doi: 10.1016/j.jare.2025.12.007.
Shize Zhang 1,  Yuang Chen 1,  Nan Aa 2,  Chen Xu 1,  Tao Xie 1,  Yi Wang 1,  Tian Cheng 1,  Mengqin Wang 1,  Hong Yu 2,  Xinqiang Ji 3,  Song Zhao 4,  Yaohui Wang 5,  Jun Xiao 6,  Yuan Xie 7,  Guangji Wang 8,  Jiye Aa 9
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
  • 2 Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, PR China.
  • 3 Digestive Endoscopy Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China.
  • 4 Department of Gastroenterology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China.
  • 5 Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China.
  • 6 Digestive Endoscopy Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China. Electronic address: [email protected].
  • 7 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China. Electronic address: [email protected].
  • 8 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China. Electronic address: [email protected].
  • 9 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China. Electronic address: [email protected].
PMID: 41371401 DOI: 10.1016/j.jare.2025.12.007
Abstract

Introduction: The repair of structural damage of the intestinal barrier is critical to rescue ulcerative colitis (UC), but there lacks effective targets currently.

Objectives: This study aims to explore mechanisms and identify potential targets for repairing the damaged intestinal barrier involved in UC.

Methods: Nontargeted metabolomic and transcriptomic analyses were utilized to characterize the metabolic features of DSS-induced colitis and identify potential therapeutic targets. Pantothenate kinase 3 (PANK3) was pharmacologically and genetically modulated to elucidate its mechanistic role. Chromatin immunoprecipitation and dual-luciferase reporter assays were employed to identify upstream regulators of PANK3, and PANK3 agonists were screened by high-throughput docking and further confirmed by in vitro and in vivo experiments.

Results: Metabolomic data indicated that perturbed metabolism involves pantothenate kinase. Clinical database, qPCR, WB, and immunohistochemical staining revealed a significant decrease of PANK3 in both patients and murine models of colitis. Pharmacological activation or overexpression of PANK3 restored the integrity of the intestinal barrier in UC mice, whereas PANK3 knockdown or inhibition exacerbated barrier dysfunction. PANK3 is negatively regulated by upstream c-Myc, and affects downstream, epithelial‒mesenchymal transition (EMT). In general, elevated c-Myc suppressed PANK3 transcription, promoted the EMT process and induced barrier disruption. The natural vitamin folic acid was identified as an agonist of PANK3, which could markedly improve the intestinal barrier in DSS-induced colitis.

Conclusion: The c-Myc-PANK3-EMT axis plays a critical role in preserving the structure and function of intestinal barrier. PANK3 is a potential target and folic acid is a candidate agonist of PANK3 to repair intestinal barrier in UC.

Keywords

EMT; Folic acid; Intestinal barrier; PANK3; Ulcerative colitis; c-Myc.

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