Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic...

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Epithelial cell metabolism is crucial in allergic inflammation and eosinophilic esophagitis (EoE) pathogenesis.
• Hypoxia-inducible factor (HIF)-1α deficiency contributes to esophageal epithelial dysfunction in EoE.
• The specific role of HIF-1α in regulating esophageal epithelial metabolism in EoE remains underexplored.

Purpose of the Study:

• To investigate the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation.
• To examine the impact on epithelial barrier function in EoE.
• To define metabolic alterations in EoE esophageal epithelium.

Main Methods:

• RNA sequencing of EoE patient biopsies to analyze metabolic gene expression (OXPHOS, glycolysis).
• Seahorse bioenergetics analysis in cell cultures to assess metabolic pathways during epithelial differentiation.
• Air-liquid interface cultures to determine metabolic dependencies for differentiation.

Main Results:

• EoE patients exhibit increased expression of oxidative phosphorylation (OXPHOS) genes.
• Differentiated epithelium relies less on OXPHOS than undifferentiated cells.
• HIF-1α knockdown cells showed reduced differentiation markers and increased OXPHOS, which was reversed by restoring HIF-1α function.

Conclusions:

• A shift towards OXPHOS-dominant metabolism in EoE is associated with impaired epithelial differentiation.
• This metabolic pattern is largely driven by reduced HIF-1α-dependent glycolysis.
• Targeting HIF-1α-mediated metabolic pathways may offer therapeutic strategies for EoE.