Selective autophagic degradation of glycolytic activator PFKFB3 contributes to maintaining intestinal epithelial barrier in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic idiopathic intestinal inflammatory disease with increasing incidence worldwide. However, the treatment of IBD is still limited and has not reached the expected therapeutic effect and new therapeutic targets are still to be discovered. Impaired autophagy and abnormal glycolysis levels were observed both in the in vivo and in vitro intestinal inflammation models, suggesting a relationship between autophagy and glycolysis in IBD. Subsequently, it demonstrated that autophagy negatively regulated the glycolysis of IECs by degradation of the key glycolytic enzyme 6‑phosphofructo‑2‑kinase/fructose‑2,6‑bisphosphatase 3 (PFKFB3). Co‑immunoprecipitation was employed to demonstrate that PFKFB3 ubiquitinated by fizzy and cell division cycle 20 related 1 E3 ligase and was then recognized by P62 autophagy receptor for degradation. Notably, increased PFKFB3 expression was detected both in patients with CD and DSS‑induced colitis. Inhibiting PFKFB3 enzyme activity relieved DSS‑induced intestinal inflammation and intestinal epithelial barrier damage. The present study proposed a combined therapy targeting autophagy and glycolysis might become a new choice for clinical treatment of IBD.