Semaphorin 3E-Plexin D1 Axis Drives Lung Fibrosis through ErbB2-Mediated Fibroblast Activation.
Summary
IPF lungs and BLM-fibrotic mouse lungs overexpress Sema3E/Plexin D1; the profibrotic P61-Sema3E isoform (generated by Furin) activates Plexin D1 and ErbB2 phosphorylation to drive fibroblast activation. Genetic or pharmacologic inhibition of Sema3E/Plexin D1/Furin reduces fibroblast activity and mitigates experimental lung fibrosis, nominating a druggable pathway.
Key Findings
- Sema3E and Plexin D1 are overexpressed in IPF patient lungs and BLM-fibrotic mice; plasma Sema3E inversely correlates with lung function.
- Furin-generated P61-Sema3E activates Plexin D1 and promotes ErbB2 phosphorylation, driving fibroblast activation, proliferation, and migration.
- Sema3E/Plexin D1 knockdown and Furin inhibition reduce fibroblast activity; whole-lung and fibroblast-specific Sema3E loss protect against BLM-induced fibrosis in vivo.
Clinical Implications
Therapeutic strategies inhibiting Furin cleavage of Sema3E, blocking Sema3E–Plexin D1 interaction, or modulating ErbB2 signaling in fibroblasts could be explored as targeted treatments for IPF.
Why It Matters
Identifies a specific ligand–receptor–kinase axis (P61-Sema3E–Plexin D1–ErbB2) driving fibroblast pathology in IPF, with convergent evidence from human samples, mechanistic cell work, and in vivo models, opening avenues for targeted anti-fibrotic therapy.
Limitations
- Translational safety and efficacy of targeting this axis in humans remain untested.
- Potential heterogeneity of Sema3E/Plexin D1 expression across IPF endotypes requires further stratification.
Future Directions
Develop selective inhibitors/antibodies against P61-Sema3E–Plexin D1 and assess anti-fibrotic efficacy, pharmacodynamics, and biomarkers in translational models and early-phase trials.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study with human tissue correlation and animal models.
- Study Design
- OTHER