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<p>Sepsis is caused by a dysregulated host response to infection, characterized by multiorgan failure in which the lung is the primary target. Although matrix metalloproteinase-9 (MMP9), a macrophage-derived protease, is known to degrade extracellular matrix proteins during inflammation, its specific role in sepsis-induced lung injury (SALI) remains to be elucidated. This study elucidates the protective function of MMP9 in SALI and validated its translational potential as an early diagnostic biomarker that integrates coagulation–inflammation crosstalk. First, we integrated human blood bulk RNA-seq data and an in-house LPS-induced murine ALI model to extract coagulation-related sepsis DEGs (Cos-Gs), constructed a PPI network, and applied two-sample Mendelian randomization (MR), which identified MMP9 as a causal protection gene. Additionally, we performed molecular docking using the ZDOCK server and 100 ns molecular dynamics simulations with Gromacs to explore the interaction between MMP9 and fibrinogen. Next, in vivo studies using CLP-operated MMP9<sup>−/−</sup> and WT mice demonstrated that MMP9 deficiency reduced survival, increased pulmonary fibrinogen accumulation, and elevated IL-6/TNF-α release. Furthermore, in macrophages, fibrinogen synergized with LPS to amplify cytokines via MAPK hyperactivation, a process that was suppressed by rmMMP9 through fibrinogen degradation and subsequent MAPK inhibition. Molecular docking results showed a ZDOCK score of 1845.832 for the interaction between MMP9 and the fibrinogen α-chain, and the 100 ns molecular dynamics simulations confirmed the MMP9–α-chain complex maintained stable RMSD (0.4 to 0.5&#xa0;nm) in a low-energy state. Finally, The ROC/XGBoost-SHAP models confirmed that MMP9 (AUC = 0.711) was the dominant predictor of SALI, outperforming IL-6 and matching TNF-α/CRP with external nomogram validation. Collectively, our findings indicated that MMP9 protects against SALI by suppressing fibrin-driven MAPK hyperactivation and cytokine release through its fibrinolytic activity, thereby establishing MMMP9 as a mechanistically grounded biomarker for early risk stratification.</p>

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Targeting inflammation and coagulation: MMP-9 deficiency exacerbates sepsis induced acute lung injury through fibrinogen-driven inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Jiabo Chen,
  • Jinquan Zhang,
  • Zhengzheng Yan,
  • Chiying Zhu,
  • Xiaona Chen,
  • Ziqi Sun,
  • Quan Li,
  • Zhixia Chen

摘要

Sepsis is caused by a dysregulated host response to infection, characterized by multiorgan failure in which the lung is the primary target. Although matrix metalloproteinase-9 (MMP9), a macrophage-derived protease, is known to degrade extracellular matrix proteins during inflammation, its specific role in sepsis-induced lung injury (SALI) remains to be elucidated. This study elucidates the protective function of MMP9 in SALI and validated its translational potential as an early diagnostic biomarker that integrates coagulation–inflammation crosstalk. First, we integrated human blood bulk RNA-seq data and an in-house LPS-induced murine ALI model to extract coagulation-related sepsis DEGs (Cos-Gs), constructed a PPI network, and applied two-sample Mendelian randomization (MR), which identified MMP9 as a causal protection gene. Additionally, we performed molecular docking using the ZDOCK server and 100 ns molecular dynamics simulations with Gromacs to explore the interaction between MMP9 and fibrinogen. Next, in vivo studies using CLP-operated MMP9−/− and WT mice demonstrated that MMP9 deficiency reduced survival, increased pulmonary fibrinogen accumulation, and elevated IL-6/TNF-α release. Furthermore, in macrophages, fibrinogen synergized with LPS to amplify cytokines via MAPK hyperactivation, a process that was suppressed by rmMMP9 through fibrinogen degradation and subsequent MAPK inhibition. Molecular docking results showed a ZDOCK score of 1845.832 for the interaction between MMP9 and the fibrinogen α-chain, and the 100 ns molecular dynamics simulations confirmed the MMP9–α-chain complex maintained stable RMSD (0.4 to 0.5 nm) in a low-energy state. Finally, The ROC/XGBoost-SHAP models confirmed that MMP9 (AUC = 0.711) was the dominant predictor of SALI, outperforming IL-6 and matching TNF-α/CRP with external nomogram validation. Collectively, our findings indicated that MMP9 protects against SALI by suppressing fibrin-driven MAPK hyperactivation and cytokine release through its fibrinolytic activity, thereby establishing MMMP9 as a mechanistically grounded biomarker for early risk stratification.