Molecular medicine (Cambridge, Mass.) · 2026
Hydrogen alleviates sepsis-associated encephalopathy via ATG9B-dependent mitophagy.
СтатьяНазвание и аннотация: Перевод в очереди
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Yu Xiaoli, Huang Xiaofan, Song Yu, Liu Jianfeng, Huang Fei, Cui Jiatian, Xie Keliang, Cui Yan
Аннотация
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.
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.