Integrated transcriptomic and experimental analyses identify SRPK1/SRSF1 as a therapeutically relevant splicing regulatory Axis in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive extracellular matrix deposition and irreversible distortion of lung architecture. We hypothesized that aberrant kinase-dependent splicing may contribute to IPF pathogenesis and offer an avenue for therapeutic intervention. We therefore analyzed multiple independent transcriptomic cohorts and found that SRPK1, compared with other SRPK family members, was most consistently elevated in fibrotic lung tissue. Higher SRPK1 expression was linked to poorer lung function and was associated with mortality after adjustment for age and sex (HR = 2.11, 95% CI: 1.10-4.04). Co-expression analysis, validation across independent cohorts, and single-cell profiling pointed to SRSF1 as a splicing factor closely associated with SRPK1 in fibrotic lungs. In lung fibroblasts, SRSF1 overexpression induced broad changes in alternative splicing. Integration of these events with human pulmonary fibrosis datasets highlighted AKT1 and KRT8 as candidate SRSF1-responsive splicing targets. We then tested the SRPK-targeting compound SPHINX31 in bleomycin-induced pulmonary fibrosis. SPHINX31 reduced hydroxyproline content, collagen deposition, myofibroblast activation, and histological fibrosis. These changes were accompanied by lower SRPK1 and SRSF1 protein levels in lung tissue. Our results link SRPK1 to disease severity and SRSF1-associated splicing changes in pulmonary fibrosis, and support further evaluation of SRPK inhibition as an antifibrotic strategy.