Transcriptomic signatures of IPF in ALI-cultured airway cells and their therapeutic implications.

Summary

Using single-cell RNA-seq of air–liquid interface airway cultures from newly diagnosed, treatment-naïve IPF, the authors delineate early epithelial–mesenchymal programs and demonstrate distinct, cell-state–specific responses to antifibrotics and the Src inhibitor saracatinib. Findings position Src pathway modulation as a promising therapeutic angle in early IPF.

Key Findings

• Single-cell profiling (129,986 transcriptomes) of ALI-cultured IPF airway mucosa identified early epithelial–mesenchymal programs and primed fibroblast states.
• Drug-perturbation revealed distinct, cell-state–specific responses to nintedanib, pirfenidone, and the Src inhibitor saracatinib.
• Data support Src pathway modulation (saracatinib) as a therapeutic strategy at the diagnostic stage of IPF.

Clinical Implications

Suggests a precision-medicine path for early IPF by targeting Src-driven epithelial–mesenchymal programs and provides a rationale for patient stratification and early-phase trials of saracatinib.

Limitations

• Ex vivo study without clinical outcome data or longitudinal validation
• Patient number not specified; generalizability and between-patient heterogeneity require confirmation

Future Directions

Prospective enrichment trials of Src inhibition with biomarker-defined airway programs; longitudinal sampling to track program dynamics and treatment response in early IPF.