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Background <p>Histone lactylation and N6-methyladenosine (m6A) alteration are epigenetic modifications that have a crucial function in controlling gene expression throughout fibroblast activation and organ fibrosis. However, their roles in sepsis-associated pulmonary fibrosis (SAPF) remain unclear.</p> Methods <p>This study established a mouse and cell model induced by lipopolysaccharides (LPS) to investigate the possible mechanisms of lactylation and METTL3-mediated m6A RNA modification in pulmonary fibroblast activation and sepsis-associated PF. The gene expression of m6A modification and lactylation in pulmonary fibroblasts of LPS-induced PF mouse model was examined using scRNA-Seq.&#xa0;Moreover, METTL3 short hairpin RNA (shRNA) and adeno-associated virus (AAV) were employed to knockdown METTL3 expression, and the glycolysis inhibitor Oxamate was utilized to attenuate lactate production and histone lactylation. Furthermore, to confirm the target gene controlled by m6A and H3K18 lactylation (H3K18la), ChIP-qPCR and RNA pulldown investigations were carried out.</p> Results <p>Single-cell RNA-sequencing unveiled the promotion of m6A modification and lactylation in pulmonary fibroblasts of LPS-induced PF mouse model. Furthermore, the induction of LPS resulted in an elevation of H3K18la lactylation and METTL3 concentrations, a reduction in PGC-1α levels, and the onset of mitochondrial dysfunction, all of which contribute to the activation of lung fibroblasts and the development of pulmonary fibrosis. Therapeutic effectiveness was observed in both in vitro and in vivo settings through focused rectification of abnormal histone lactylation or by reducing the expression of METTL3.</p> Conclusion <p>Our study demonstrates, LPS-induced histone lactylation contributes to sepsis-induced pulmonary fibrosis by upregulating METTL3 expression. Additionally, METTL3 recognizes m6A-modified PGC-1α mRNAs, leading to mitochondrial dysfunction and accelerated fibroblast activation, ultimately driving pulmonary fibrosis. METTL3-mediated m6A modification potently degraded PGC-1α, leading to mitochondrial dysfunction and accelerated fibroblast activation, ultimately driving Sepsis-Associated PF. This suggests that the presence of histone lactylation in the fibrotic microenvironment associated with sepsis plays a crucial role in triggering the expression and activity of the RNA methyltransferase METTL3.</p>

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Lipopolysaccharide-induced histone lactylation mediates m6A RNA modification causing mitochondrial dysfunction and pulmonary fibroblasts activation to exacerbate sepsis-associated pulmonary fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月16日

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  • Ri Tang,
  • Shaojie Qin,
  • Qiaoyi Xu,
  • Wenyu Lin,
  • Shuyi Zhang,
  • Yawen Peng,
  • Jinhua Feng,
  • Shunpeng Xing,
  • Yuan Gao,
  • Shuya Mei,
  • Zhengyu He

摘要

Background

Histone lactylation and N6-methyladenosine (m6A) alteration are epigenetic modifications that have a crucial function in controlling gene expression throughout fibroblast activation and organ fibrosis. However, their roles in sepsis-associated pulmonary fibrosis (SAPF) remain unclear.

Methods

This study established a mouse and cell model induced by lipopolysaccharides (LPS) to investigate the possible mechanisms of lactylation and METTL3-mediated m6A RNA modification in pulmonary fibroblast activation and sepsis-associated PF. The gene expression of m6A modification and lactylation in pulmonary fibroblasts of LPS-induced PF mouse model was examined using scRNA-Seq. Moreover, METTL3 short hairpin RNA (shRNA) and adeno-associated virus (AAV) were employed to knockdown METTL3 expression, and the glycolysis inhibitor Oxamate was utilized to attenuate lactate production and histone lactylation. Furthermore, to confirm the target gene controlled by m6A and H3K18 lactylation (H3K18la), ChIP-qPCR and RNA pulldown investigations were carried out.

Results

Single-cell RNA-sequencing unveiled the promotion of m6A modification and lactylation in pulmonary fibroblasts of LPS-induced PF mouse model. Furthermore, the induction of LPS resulted in an elevation of H3K18la lactylation and METTL3 concentrations, a reduction in PGC-1α levels, and the onset of mitochondrial dysfunction, all of which contribute to the activation of lung fibroblasts and the development of pulmonary fibrosis. Therapeutic effectiveness was observed in both in vitro and in vivo settings through focused rectification of abnormal histone lactylation or by reducing the expression of METTL3.

Conclusion

Our study demonstrates, LPS-induced histone lactylation contributes to sepsis-induced pulmonary fibrosis by upregulating METTL3 expression. Additionally, METTL3 recognizes m6A-modified PGC-1α mRNAs, leading to mitochondrial dysfunction and accelerated fibroblast activation, ultimately driving pulmonary fibrosis. METTL3-mediated m6A modification potently degraded PGC-1α, leading to mitochondrial dysfunction and accelerated fibroblast activation, ultimately driving Sepsis-Associated PF. This suggests that the presence of histone lactylation in the fibrotic microenvironment associated with sepsis plays a crucial role in triggering the expression and activity of the RNA methyltransferase METTL3.