Hypoxia induces a glycolytic complex in inflammatory bowel disease independent of RNA

Chronic mucosal inflammation in inflammatory bowel disease (IBD) creates a profoundly hypoxic environment that alters epithelial cell metabolism with profound implications for epithelial cell barrier function. Hypoxia stabilizes the hypoxia-inducible factor-1α (HIF-1α) which drives an adaptive metabolic shift towards increased glycolysis, enabling cells to maintain ATP levels when mitochondrial oxidative phosphorylation is reduced due to a lack of oxygen availability. We have shown that hypoxia can also induce the formation of glycolytic complexes that may facilitate substrate channelling, improved metabolic efficiency and cell survival in hypoxia (Kierans et al. 2023). In this study, we investigated for the first time whether these glycolytic complexes formed in healthy and inflamed human mucosal tissue. Work by other groups have suggested a role for long non-coding RNA molecules (lncRNA) as scaffolds for glycolytic complexes. Therefore, we also investigated the possible role of lncRNAs in the formation of glycolytic complexes in IBD. We identified for the first time in vivo, the presence of glycolytic complexes in colonic biopsies collected from control individuals and IBD patients using both immunofluorescence (IF) and proximity ligation assay (PLA). Next, we investigated what microenvironmental feature is driving the formation of these glycolytic complexes in intestinal epithelial cells. We found that hypoxia, rather than inflammation, is the main microenvironmental driver of glycolytic complex formation and glycolytic activity, as confirmed by immunoprecipitation of PFKP followed by HK2 western blot, and via lactate assays. We next investigated whether lncRNAs might contribute to the formation of a hypoxia-induced glycolytic complex. These experiments revealed that disruption of RNA did not impair hypoxia-induced glycolytic complex formation in intestinal epithelial cells. In summary, we have demonstrated that hypoxia induces a glycolytic complex in vivo and that hypoxia induces a glycolytic complex in intestinal epithelial cells independently of RNA. Understanding the drivers and mechanisms of intestinal epithelial cell metabolism will allow us to identify new epithelium-directed therapeutic targets for IBD. 1) Kierans, S.J., et al., Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression. Proc Natl Acad Sci U S A, 2023. 120(35): p. e2208117120. Funding agencies: Research Ireland (Taighde Éireann). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.