https://doi.org/10.1016/j.apsb.2025.04.017
This new article publication from Acta Pharmaceutica Sinica B, discusses how SRSF7 promotes pulmonary fibrosis through regulating PKM alternative splicing in lung fibroblasts.
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, an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) was identified 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.
It was demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, alternative splicing events were investigated 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, lomitapide was identified as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis.
Collectively, these findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.
Keywords: IPF, Alternative splicing, Splicing factor, SRSF7, PKM, Fibroblasts, Metabolism, Drug screening
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525002746-ga1_lrg.jpg
SRSF7 regulates the alternative splicing of PKM, leading to dysregulation of glycolysis and activation of fibroblasts. This study highlights targeting the SRSF7–PKM axis as a promising therapeutic strategy for IPF.
