美国哥伦比亚大学阙建文等研究人员合作发现，RUNX2通过肺泡向病理性成纤维细胞转变促进纤维化。这一研究成果于2025年2月5日在线发表在国际学术期刊《自然》上。

研究人员使用两种肺纤维化小鼠模型来证明，在肺泡生成过程中出现的LEPR⁺成纤维细胞，包括SCUBE2⁺肺泡成纤维细胞，作为主要组成部分。这些肺泡成纤维细胞进而显著贡献于CTHRC1⁺POSTN⁺病理性成纤维细胞。基因消融POSTN⁺病理性成纤维细胞可减轻纤维化。

对scRNA-seq和scATAC-seq数据的综合分析表明，RUNX2是纤维化基因表达的关键调控因子。与此一致地，使用Lepr^creERT2或Scube2^creERT2条件性删除Runx2可减少病理性成纤维细胞的生成、细胞外基质沉积和肺纤维化。因此，包括SCUBE2⁺肺泡成纤维细胞在内的LEPR⁺细胞是病理性成纤维细胞的关键来源，而靶向Runx2为肺纤维化提供了潜在的治疗选择。

据悉，肺纤维化的一个标志是肺成纤维细胞异常激活为病理性成纤维细胞，这些细胞产生过多的细胞外基质。因此，识别促进病理性成纤维细胞生成的关键调控因子，可以为开发有效的疾病进展对策提供依据。

附：英文原文

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

Author: Fang, Yinshan, Chung, Sanny S. W., Xu, Le, Xue, Chenyi, Liu, Xue, Jiang, Dianhua, Li, Rongbo, Korogi, Yohei, Yuan, Ke, Saqi, Anjali, Hibshoosh, Hanina, Huang, Yuefeng, Lin, Chyuan-Sheng, Tsukui, Tatsuya, Sheppard, Dean, Sun, Xin, Que, Jianwen

Issue&Volume: 2025-02-05

Abstract: A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix1,2,3. 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.

DOI: 10.1038/s41586-024-08542-2

Source: https://www.nature.com/articles/s41586-024-08542-2