Hydrogen Gas Inhalation Protects the Brain During Sepsis and Improves Survival
- Authors
- Xiaoli Yu, Xiaofan Huang, Yu Song, Jianfeng Liu, Fei Huang, Jiatian Cui, Keliang Xie, Yan Cui
- Journal
- Molecular Medicine
- Year
- 2026
- DOI
- 10.1186/s10020-026-01566-6
- Study Type
- Mouse
- Outcome
- Positive
- Peer Reviewed
- Yes
- Country
- China
- Health Condition
- Sepsis-Associated Encephalopathy
- Body System
- Nervous System
TL;DR
Hydrogen inhalation improved survival and cognition in septic mice by enhancing ATG9B-dependent clearance of damaged mitochondria.
Key Finding
Mice with sepsis-induced brain injury that received hydrogen gas inhalation showed a 75% survival rate compared to 40% in untreated mice, along with reduced brain inflammation and preserved cognitive function.
Summary
This study tested whether inhaled hydrogen gas could protect the brain during sepsis (a life-threatening infection). Researchers induced sepsis in mice and gave some of them hydrogen gas to breathe. They found that hydrogen improved survival rates, reduced brain inflammation, and prevented cognitive problems. The study identified that hydrogen works by activating a cellular cleanup process called mitophagy (where cells remove damaged energy-producing structures called mitochondria), which protects brain cells from dying.
Practical Takeaway
While this is an early-stage animal study showing hydrogen gas may protect brain function during severe infection, it does not yet demonstrate whether these effects occur in humans. The findings suggest a potential mechanism worth investigating further, but much more research—including human trials—would be needed before hydrogen inhalation could be considered a treatment for sepsis-related cognitive problems.
Abstract
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.