Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.
SRSF7 promotes pulmonary fibrosis through regulating PKM alternative splicing in lung fibroblasts.
阅读:3
作者:Jin Tongzhu, Gao Huiying, Wang Yuquan, Ning Zhiwei, Bing Danyang, Wang Yan, Chen Yi, Tian Xiaomu, Liu Qiudi, Niu Zhihui, Guo Jiayu, Sun Jian, Yang Ruoxuan, Wang Qianqian, Li Shifen, Li Tianyu, Zhou Yuhong, He Wenxin, Lu Yanjie, Gu Yunyan, Liang Haihai
期刊: | Acta Pharmaceutica Sinica B | 影响因子: | 14.600 |
时间: | 2025 | 起止号: | 2025 Jun;15(6):3041-3058 |
doi: | 10.1016/j.apsb.2025.04.017 |
特别声明
1、本文转载旨在传播信息,不代表本网站观点,亦不对其内容的真实性承担责任。
2、其他媒体、网站或个人若从本网站转载使用,必须保留本网站注明的“来源”,并自行承担包括版权在内的相关法律责任。
3、如作者不希望本文被转载,或需洽谈转载稿费等事宜,请及时与本网站联系。
4、此外,如需投稿,也可通过邮箱info@biocloudy.com与我们取得联系。