Fndc5 Modification Optimizes the Therapeutic Effect of Rat Mesenchymal Stem Cells on Sepsis-Induced Acute Lung Injury/Acute Respiratory Distress Syndrome via Activating the PI3K/AKT Signaling Pathway

• • Fndc5 modification increased MSC retention in LPS-injured lungs by >2-fold (p < 0.001), directly addressing the <5% engraftment efficiency that limits clinical MSC therapy. • • MSCs-Fndc5 reduced lung wet-to-dry weight ratio by ~30% versus unmodified MSCs (p < 0.01), indicating resolution of pulmonary edema—a key ARDS mortality driver. • • Co-culture with MSCs-Fndc5 restored VE-cadherin and β-catenin expression in LPS-injured endothelial cells (p < 0.001), reversing adherens junction disassembly and barrier permeability. • • The PI3K inhibitor LY294002 abolished MSCs-Fndc5-mediated endothelial protection (p < 0.001), confirming that PI3K/AKT activation is necessary for the therapeutic effect.