Tanshinone IIA attenuates sepsis-induced lung injury by reducing VEGFR2/PI3K/AKT-driven mitochondrial disruption dependent apoptosis.

BACKGROUND

Sepsis-induced lung injury (SILI) is marked by excessive inflammation and apoptosis, posing considerable therapeutic problems owing to the scarcity of targeted therapy. Tanshinone IIA (TanIIA), a bioactive molecule extracted from Salvia miltiorrhiza, demonstrates potential in regulating inflammatory pathways and enhancing cellular resilience.

PURPOSE

This study comprehensively examined the therapeutic mechanisms of TanIIA in SILI by an integrated methodology that incorporates network pharmacology, molecular docking, and comprehensive experimental validation.

METHODS

Network pharmacology and WGCNA analysis of GSE239388 revealed possible treatment targets for TanIIA. Computational analysis utilizing molecular docking techniques and molecular dynamics simulations validated a stable intermolecular connection between TanIIA and the vascular endothelial growth factor receptor 2. TanIIA's therapeutic effectiveness was evaluated in vivo using septic mouse model. BEAS-2B cells treated with LPS in vitro were employed to elucidate the underlying mechanisms. Western blotting, qRT-PCR, immunohistochemistry, flow cytometry, and mitochondrial function assays were performed to evaluate gene expression, apoptosis, and mitochondrial functionality.

RESULTS

VEGFR2 was identified as a critical therapeutic target of TanIIA in SILI. Treatment with TanIIA significantly enhanced survival rates, mitigated lung histopathological damage, and decreased levels of pro-inflammatory cytokines in CLP-induced septic mice. Mechanistically, TanIIA suppressed the VEGFR2-PI3K-AKT signaling pathway, preserving mitochondrial integrity and inhibiting apoptosis. Additional validation was obtained using LPS-treated BEAS-2B epithelial cells, reinforcing the initial findings.

CONCLUSION

TanIIA provides protective effects against SILI by specifically targeting VEGFR2 and inhibiting the PI3K/AKT signaling pathway, which helps maintain mitochondrial homeostasis and reduces apoptosis.