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Targeting the S100A2-RAGE Pathway Restores AT2 Cell Identity and Mitigates Lung Fibrosis
Changli Zhou1, Jack H Wellmerling2, Alireza Jian Bagherpoor1
1The Hormel Institute, University of Minnesota, Austin, MN, United States.
American Journal of Respiratory Cell and Molecular Biology
|August 11, 2026
Summary
S100A2 drives lung fibrosis by causing alveolar type 2 cell loss and aberrant reprogramming. Targeting the S100A2-RAGE pathway with Azeliragon may restore lung epithelial homeostasis and reduce fibrosis.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Molecular Biology
Background:
- Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), involves disrupted epithelial repair and fibroblast activation.
- Loss of alveolar type 2 (AT2) cell identity and aberrant transitional states impair lung regeneration in fibrosis.
- S100A2 is upregulated in IPF lungs and associated with AT2 cell reprogramming.
Purpose of the Study:
- Investigate the role of S100A2 in lung fibrosis pathogenesis.
- Determine the functional consequences of S100A2 overexpression in AT2 cells.
- Evaluate the therapeutic potential of targeting the S100A2-RAGE pathway.
Main Methods:
- Re-analysis of scRNA-seq datasets from the IPF Cell Atlas.
- Co-culture of human AT2 cells with fibroblasts in lung organoid models.
- Overexpression of S100A2 in iPSC-derived AT2 (iAT2) cells.
- Pharmacologic inhibition of RAGE using Azeliragon in bleomycin-induced lung fibrosis models.
Main Results:
- S100A2 expression correlates with basal-like reprogramming of AT2 cells in IPF.
- S100A2 overexpression in iAT2 cells causes loss of AT2 identity, increased ROS, and RAGE pathway activation.
- Azeliragon treatment preserves AT2 cells, reduces oxidative stress, and attenuates collagen deposition in fibrotic lungs.
Conclusions:
- S100A2 is a key driver of epithelial dysfunction in lung fibrosis, promoting AT2 cell identity loss and injury.
- The S100A2-RAGE pathway represents a novel therapeutic target for restoring lung epithelial homeostasis.
- Targeting this pathway offers a potential new strategy for treating lung fibrosis.
