SRSF7 promotes pulmonary fibrosis through regulating PKM alternative splicing in lung fibroblasts.

Tongzhu JIN; Huiying GAO; Yuquan WANG; Zhiwei NING; Danyang BING; Yan WANG; Yi CHEN; Xiaomu TIAN; Qiudi LIU; Zhihui NIU; Jiayu GUO; Jian SUN; Ruoxuan YANG; Qianqian WANG; Shifen LI; Tianyu LI; Yuhong ZHOU; Wenxin HE; Yanjie LU; Yunyan GU; Haihai LIANG

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SRSF7 promotes pulmonary fibrosis through regulating PKM alternative splicing in lung fibroblasts.

Author: Tongzhu JIN ¹ ; Huiying GAO ¹ ; Yuquan WANG ¹ ; Zhiwei NING ¹ ; Danyang BING ¹ ; Yan WANG ¹ ; Yi CHEN ¹ ; Xiaomu TIAN ¹ ; Qiudi LIU ¹ ; Zhihui NIU ¹ ; Jiayu GUO ¹ ; Jian SUN ² ; Ruoxuan YANG ¹ ; Qianqian WANG ¹ ; Shifen LI ¹ ; Tianyu LI ¹ ; Yuhong ZHOU ³ ; Wenxin HE ⁴ ; Yanjie LU ¹ ; Yunyan GU ¹ ; Haihai LIANG ¹
Author Information

1. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
2. Translational Medicine Research Center, Medical Pathology Center, Chongqing University Three Gorges Hospital, School of Medicine Chongqing University, Chongqing University, Chongqing 400000, China.
3. Department of Basic Medicine, Xiamen Medical College, Xiamen 361023, China.
4. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.
Publication Type:Journal Article
Keywords: Alternative splicing; Drug screening; Fibroblasts; IPF; Metabolism; PKM; SRSF7; Splicing factor
From: Acta Pharmaceutica Sinica B 2025;15(6):3041-3058
CountryChina
Language:English
Abstract: 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.