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Background <p>Sepsis is a severe inflammatory condition often complicated by acute lung injury (ALI) with limited therapeutic options. S100 Calcium Binding Protein A9 (S100A9) as an alarmin is highly elevated in sepsis. We observed that S100A9 was lactylated in the lung tissues of septic mice, the role of which in regulating sepsis-related ALI remains unknown.<!--Query ID="Q1" Text="Kindly check and confirm whether the corresponding author is correctly identified and amend if necessary. " Resolved="yes"--><!--Query ID="Q2" Text="Please confirm if the author names are presented accurately and in the correct sequence. " Resolved="yes"--><!--Query ID="Q3" Text="Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. " Resolved="yes"--><!--Query ID="Q4" Text="Please check if the affiliations are captured and presented correctly. Otherwise, amend if necessary. " Resolved="yes"--><!--Query ID="Q5" Text="Please check the article title if captured and presented correctly. Otherwise amend if deemed necessary. " Resolved="yes"--></p> Methods <p>S100A9 lactylation sites were identified in septic patients and CLP mice using immunoprecipitation and mass spectrometry. Mechanistic studies employed mutagenesis, co-immunoprecipitation, and luciferase assays.</p> Results <p>In this study, we confirmed that S100A9 was lactylated at K4 and K94 in septic patients. Lactylated S100A9 promoted its nuclear translocation, thereby enhancing its interaction with transcription factor CCAAT/enhancer-binding protein beta (Cebpb). The complex of S100A9 and Cebpb further promoted the transcriptional activation of downstream interleukin 1 beta (IL-1β), leading to sepsis-related ALI. Moreover, the knockout of S100A9 effectively alleviated sepsis-induced inflammatory response and lung injury.</p> Conclusions <p>Our findings elucidated the importance of S100A9 lactylation in regulating inflammatory responses of macrophages in sepsis-induced ALI, providing novel insights into the pathophysiology of sepsis and potential therapeutic targets for sepsis-associated organ dysfunction.</p>

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S100A9 lactylation facilitated sepsis-related acute respiratory distress syndrome via promoting transcription activation of IL-1β in macrophages

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Xiangtao Zheng,
  • Wen Xu,
  • Fangchen Gong,
  • Shunwei Huang,
  • Xiaofeng Wang,
  • Shanzhi Zhao,
  • Yu Han,
  • Huan Liu,
  • Lei Pei,
  • Dan Xu,
  • Zhitao Yang,
  • Enqiang Mao,
  • Ranran Li,
  • Ying Chen,
  • Erzhen Chen

摘要

Background

Sepsis is a severe inflammatory condition often complicated by acute lung injury (ALI) with limited therapeutic options. S100 Calcium Binding Protein A9 (S100A9) as an alarmin is highly elevated in sepsis. We observed that S100A9 was lactylated in the lung tissues of septic mice, the role of which in regulating sepsis-related ALI remains unknown.

Methods

S100A9 lactylation sites were identified in septic patients and CLP mice using immunoprecipitation and mass spectrometry. Mechanistic studies employed mutagenesis, co-immunoprecipitation, and luciferase assays.

Results

In this study, we confirmed that S100A9 was lactylated at K4 and K94 in septic patients. Lactylated S100A9 promoted its nuclear translocation, thereby enhancing its interaction with transcription factor CCAAT/enhancer-binding protein beta (Cebpb). The complex of S100A9 and Cebpb further promoted the transcriptional activation of downstream interleukin 1 beta (IL-1β), leading to sepsis-related ALI. Moreover, the knockout of S100A9 effectively alleviated sepsis-induced inflammatory response and lung injury.

Conclusions

Our findings elucidated the importance of S100A9 lactylation in regulating inflammatory responses of macrophages in sepsis-induced ALI, providing novel insights into the pathophysiology of sepsis and potential therapeutic targets for sepsis-associated organ dysfunction.