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

  • Phytomedicine. 2025 Jun 14:145:156957. doi: 10.1016/j.phymed.2025.156957.
Delida Aidebaike  1 ,  Hailong Gong  1 ,  Yun Xia  1 ,  Guoqing Jing  1 ,  Huifan Liu  1 ,  Huimin Zhou  1 ,  Die Wu  1 ,  Jing Zuo  1 ,  Cheng Yang  1 ,  Xing Wang  1 ,  Yingyue Dong  1 ,  Jie Yan  1 ,  Xue Chen  2 ,  Zihan Lei  2 ,  Junjie Liang  1 ,  Xiaojing Wu  3 ,  Xuemin Song  4
Affiliations
  • 1. Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China.
  • 2. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China.
  • 3. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China. Electronic address: [email protected].
  • 4. Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China. Electronic address: [email protected].
PMID: 40544732 DOI: 10.1016/j.phymed.2025.156957
Abstract

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.

Keywords
Apoptosis; Mitochondrial disruption; Network pharmacology; Sepsis-induced lung injury; TanshinoneIIA; VEGFR2.
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