Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis

This study uses spatial metabolomics to analyze metabolic heterogeneity in human lung diseases. It identifies metabolic channeling between glycogen and N-linked glycans as a critical process favoring pulmonary fibrosis progression. The research demonstrates that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. The study employs high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets. This approach helps to map tissue anatomical regions and identify unique carbohydrate features that predict fibrotic tissue. Genetically modified mouse models with lysosomal glycogen utilization deficiency displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis. This suggests that glycogen metabolism plays a significant role in the development of pulmonary fibrosis.

• 1
  High-dimensionality reduction and spatial clustering (HDR-SC) of MALDI-MSI datasets can accurately identify tissue microanatomy in both healthy and diseased lung tissues.
• 2
  Glycogen and core fucosylated N-linked glycans are identified as clinical hallmarks of pulmonary fibrosis and are uniquely present in the myofibroblast cellular population.
• 3
  Inability to utilize glycogen, either through genetic modification or enzyme deficiency, blunts fibrosis development in vivo, suggesting glycogen utilization is necessary for fibrosis progression.