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Molecular hydrogen-mediated SIRT1 activation alleviates sepsis-associated encephalopathy by promoting mitophagy.

分子状水素によるSIRT1活性化が敗血症関連脳症においてミトファジーを促進することで神経保護効果を発揮する

animal study inhalation positive 2%

Abstract

A cecal ligation and puncture (CLP) mouse model of sepsis-associated encephalopathy (SAE) was used to examine the effects of 2% hydrogen gas inhalation. Seven-day survival improved from 50% to 75% (P < 0.01), and cognitive performance in the Morris water maze was enhanced, with increased platform crossings and shortened escape latency. Proteomic profiling combined with Western blotting, immunofluorescence, and electron microscopy revealed that hydrogen upregulated SIRT1 expression and activated PINK1/Parkin-dependent mitophagy. Downstream consequences included reduced STING phosphorylation, lower levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and diminished neuronal apoptosis in the hippocampal CA1 region. Administration of the SIRT1 inhibitor EX527 abolished these protective outcomes, confirming that SIRT1-mediated mitophagy is the central mechanism through which hydrogen mitigates neuroinflammation and neuronal loss in SAE.

Mechanism

Hydrogen activates SIRT1, which promotes PINK1/Parkin-dependent mitophagy, leading to suppressed STING phosphorylation, reduced pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α), and decreased neuronal apoptosis in the hippocampal CA1 region.

Bibliographic

Authors
Meng S, Wang Z, Fan Y, Pei S, Cui J, Liu J, et al.
Journal
Eur J Med Res
Year
2025 (2025-12-05)
PMID
41351127
DOI
10.1186/s40001-025-03600-5
PMC
PMC12829070

Tags

Disease:sepsis (48) Delivery:inhalation delivery (196) Mechanism:apoptosis regulation (280) autophagy (32) anti-inflammatory (743) mitochondrial function (226) oxidative stress (899)

Delivery context

In air, molecular hydrogen is reported to be combustible across approximately **4% (LFL, lower flammability limit) to 75% (UFL, upper flammability limit)**. Among high-concentration hydrogen inhalers, 66% output sits inside this range, and even pure-hydrogen (100%) output forms a 4–75% concentration-gradient layer at the device–air boundary (the UFL 75% paradox). Engineering principle would therefore call for operation below LFL (the classical 4%); that figure, however, was measured under closed, pre-mixed, static conditions. For the open, dynamic inhalation environment, the empirical value reported in the literature is **10%**, which is the figure referenced in practice as the operating ceiling. The 66% / 100% output devices are recorded in the Japanese Consumer Affairs Agency accident-information database, and from these considerations are not recommended.

→ Evidence by delivery route

Safety notes

In air, molecular hydrogen is reported to be combustible across approximately **4% (LFL, lower flammability limit) to 75% (UFL, upper flammability limit)**. Among high-concentration hydrogen inhalers, 66% output sits inside this range, and even pure-hydrogen (100%) output forms a 4–75% concentration-gradient layer at the device–air boundary (the UFL 75% paradox). Engineering principle would therefore call for operation below LFL (the classical 4%); that figure, however, was measured under closed, pre-mixed, static conditions. For the open, dynamic inhalation environment, the empirical value reported in the literature is **10%**, which is the figure referenced in practice as the operating ceiling. The 66% / 100% output devices are recorded in the Japanese Consumer Affairs Agency accident-information database, and from these considerations are not recommended.

See also:

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