FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury.

Summary

Using conditional genetics and pharmacology, the authors show that FGF13 scaffolds TAK1/MEK/ERK signaling to amplify HIF‑1α–driven aerobic glycolysis in endothelial cells and macrophages, thereby worsening septic lung injury. ERK inhibition abrogated FGF13-induced inflammation, and HIF‑1α overexpression reversed protection from Fgf13 deletion.

Key Findings

• FGF13 is downregulated in lung endothelial cells and macrophages of septic patients and mice.
• Conditional Fgf13 deletion protects against, and overexpression worsens, septic lung inflammation.
• FGF13 scaffolds TAK1/MEK/ERK to enhance HIF‑1α–regulated aerobic glycolysis under inflammatory conditions.
• ERK inhibitor SCH772984 abolishes FGF13-driven inflammatory exacerbation; HIF‑1α overexpression negates protection from Fgf13 knockout.

Clinical Implications

Suggests therapeutic potential for ERK pathway inhibitors or targeting FGF13-driven glycolysis to mitigate septic lung injury; FGF13 expression could inform risk stratification.

Limitations

• Preclinical models (murine sepsis) may not fully recapitulate human pathophysiology.
• Translational feasibility of targeting FGF13 or ERK/HIF‑1α in acute sepsis remains to be established.

Future Directions

Validate FGF13 as a biomarker and therapeutic target in human sepsis cohorts; test ERK/HIF‑1α/glycolysis modulators in clinically relevant models and early-phase trials.