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Background <p>Sepsis-associated encephalopathy (SAE) is a severe complication with high mortality and limited therapeutic options. Molecular hydrogen (H₂) has shown neuroprotective potential, but its mechanism remains elusive.</p> Methods <p>SAE was induced in C57BL/6J mice by cecal ligation and puncture, with or without 2% H<sub>2</sub> inhalation. HT22 hippocampal neurons were challenged with lipopolysaccharide in hydrogen-rich medium. H₂ intervention was administered via inhalation or hydrogen-rich medium. Cognitive function was evaluated by novel object recognition and Y-maze tests.</p> <p>Transcriptome sequencing was used to identify key signaling pathways regulated by H₂. The neuroprotective mechanism of H₂ was explored by assessing mitophagy, apoptosis, reactive oxygen species, and mitochondrial membrane potential. ATG9B was knocked down using siRNA in vitro and AAV-shRNA in the hippocampal CA1 region in vivo to clarify its function.</p> Results <p>H₂ inhalation increased 7-day survival in CLP-induced septic mice from 40% to 75%, reduced systemic and hippocampal pro-inflammatory cytokines, and alleviated hippocampal neuronal damage and cognitive dysfunction. Transcriptomic profiling identified ATG9B as the most significantly upregulated mitophagy-related gene by H2. Mechanistically, H₂ upregulated ATG9B expression, which in turn enhanced PINK1-Parkin-mediated mitophagy flux, thereby coordinating mitophagosome formation and lysosomal fusion, leading to clearance of damaged mitochondria and reduced neuronal apoptosis. ATG9B knockdown completely abolished H₂-induced mitophagy flux, mitochondrial protection, and cognitive improvement.</p> Conclusions <p>H₂ alleviates SAE by upregulating ATG9B and restoring PINK1-Parkin-dependent mitophagy. The ATG9B-mitophagy axis represents a novel therapeutic target, and H₂ inhalation emerges as a potential strategy for sepsis-associated cognitive impairment.</p>

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Hydrogen alleviates sepsis-associated encephalopathy via ATG9B-dependent mitophagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Xiaoli Yu,
  • Xiaofan Huang,
  • Yu Song,
  • Jianfeng Liu,
  • Fei Huang,
  • Jiatian Cui,
  • Keliang Xie,
  • Yan Cui

摘要

Background

Sepsis-associated encephalopathy (SAE) is a severe complication with high mortality and limited therapeutic options. Molecular hydrogen (H₂) has shown neuroprotective potential, but its mechanism remains elusive.

Methods

SAE was induced in C57BL/6J mice by cecal ligation and puncture, with or without 2% H2 inhalation. HT22 hippocampal neurons were challenged with lipopolysaccharide in hydrogen-rich medium. H₂ intervention was administered via inhalation or hydrogen-rich medium. Cognitive function was evaluated by novel object recognition and Y-maze tests.

Transcriptome sequencing was used to identify key signaling pathways regulated by H₂. The neuroprotective mechanism of H₂ was explored by assessing mitophagy, apoptosis, reactive oxygen species, and mitochondrial membrane potential. ATG9B was knocked down using siRNA in vitro and AAV-shRNA in the hippocampal CA1 region in vivo to clarify its function.

Results

H₂ inhalation increased 7-day survival in CLP-induced septic mice from 40% to 75%, reduced systemic and hippocampal pro-inflammatory cytokines, and alleviated hippocampal neuronal damage and cognitive dysfunction. Transcriptomic profiling identified ATG9B as the most significantly upregulated mitophagy-related gene by H2. Mechanistically, H₂ upregulated ATG9B expression, which in turn enhanced PINK1-Parkin-mediated mitophagy flux, thereby coordinating mitophagosome formation and lysosomal fusion, leading to clearance of damaged mitochondria and reduced neuronal apoptosis. ATG9B knockdown completely abolished H₂-induced mitophagy flux, mitochondrial protection, and cognitive improvement.

Conclusions

H₂ alleviates SAE by upregulating ATG9B and restoring PINK1-Parkin-dependent mitophagy. The ATG9B-mitophagy axis represents a novel therapeutic target, and H₂ inhalation emerges as a potential strategy for sepsis-associated cognitive impairment.