RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition

Yinshan Fang, Sanny S. W. Chung, Le Xu, Chenyi Xue, Xue Liu, Dianhua Jiang, Rongbo Li, Yohei Korogi, Ke Yuan, Anjali Saqi, Hanina Hibshoosh, Yuefeng Huang, Chyuan-Sheng Lin, Tatsuya Tsukui, Dean Sheppard, Xin Sun () and Jianwen Que ()
Additional contact information
Yinshan Fang: Columbia University Irving Medical Center
Sanny S. W. Chung: Columbia University Irving Medical Center
Le Xu: University of California San Diego
Chenyi Xue: Columbia University Irving Medical Center
Xue Liu: Cedars-Sinai Medical Center
Dianhua Jiang: Cedars-Sinai Medical Center
Rongbo Li: University of California San Diego
Yohei Korogi: University of California San Diego
Ke Yuan: Boston Children’s Hospital and Harvard Medical School
Anjali Saqi: Columbia University Irving Medical Center
Hanina Hibshoosh: Columbia University Irving Medical Center
Yuefeng Huang: Columbia University
Chyuan-Sheng Lin: Columbia University
Tatsuya Tsukui: University of California San Francisco
Dean Sheppard: University of California San Francisco
Xin Sun: University of California San Diego
Jianwen Que: Columbia University Irving Medical Center

Nature, 2025, vol. 640, issue 8057, 221-230

Abstract: Abstract A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix1–3. Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR+ fibroblasts that arise during alveologenesis include SCUBE2+ alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1+POSTN+ pathological fibroblasts. Genetic ablation of POSTN+ pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with LeprcreERT2 or Scube2creERT2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR+ cells that include SCUBE2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.

Date: 2025
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DOI: 10.1038/s41586-024-08542-2

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