FGF20 activates FGFR1-PI3K-AKT signaling to coordinate barrier integrity and alveolar coagulation in sepsis-induced lung injury.

Summary

In a CLP rat model of sepsis-induced ALI, recombinant human FGF20 improved 7-day survival, reduced edema/inflammation, restored gas exchange, and preserved alveolar-capillary junctions. Mechanistically, FGF20 signaled via FGFR1–PI3K–AKT to inhibit NF-κB and TF/PAI-1 while stabilizing E-/VE-cadherin and ZO-1; FGFR1 or AKT inhibition abrogated benefits. In ARDS patients, serum/BAL FGF20 levels were reduced and positively correlated with PaO2/FiO2.

Key Findings

• Recombinant human FGF20 improved 7-day survival and reduced edema/inflammation in a CLP rat model while preserving gas exchange and barrier integrity.
• FGF20 engaged FGFR1–PI3K–AKT signaling to inhibit NF-κB and TF/PAI-1 transcription and to stabilize E-cadherin, VE-cadherin, and ZO-1 via GSK3β Ser9 phosphorylation.
• Pharmacologic inhibition of FGFR1 or AKT abolished both barrier-protective and anticoagulant effects, confirming pathway dependency.
• In ARDS patients, serum and BAL FGF20 levels were reduced and positively correlated with PaO2/FiO2, linking lower FGF20 to disease severity.

Clinical Implications

Restoring the FGF20–FGFR1 axis could stabilize the alveolar-capillary barrier and dampen immunothrombosis in sepsis-induced ALI/ARDS. This supports biomarker-guided early-phase trials of recombinant FGF20 or FGFR1–AKT modulators.

Limitations

• Preclinical animal model may not fully translate to human ARDS pathophysiology and treatment responses.
• Clinical data are observational with unspecified sample size, limiting inference on causality and generalizability.

Future Directions

Conduct dose-finding and safety trials of recombinant FGF20 in sepsis-induced ARDS, validate FGF20 as a predictive biomarker, and explore combination strategies with anticoagulant and barrier-stabilizing therapies.