# Mechanism by which hydrogen-rich water mitigates exercise-induced fatigue: activation of the immunoresponsive gene 1-itaconate/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.
> 水素水による運動誘発性疲労軽減のメカニズム：IRG1-イタコン酸/Nrf2/HO-1経路の活性化


## Abstract

Using a mouse model of exercise-induced fatigue, this study investigated the molecular mechanisms underlying the fatigue-reducing effects of hydrogen-rich water. Administration of hydrogen-rich water improved motor function and reduced fatigue-associated biomarkers including blood urea nitrogen, lactate, and creatine kinase, while also attenuating gastrocnemius muscle damage. Ultrahigh-performance liquid chromatography-mass spectrometry analysis revealed that hydrogen-rich water elevated immunoresponsive gene 1 (IRG1) expression, restored fatigue-suppressed itaconic acid levels, and subsequently activated the downstream Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Complementary experiments in C2C12 cells using an IRG1 inhibitor or 4-octyl itaconic acid confirmed that hydrogen-rich water upregulated Nrf2 and HO-1 expression at the cellular level. Collectively, these findings indicate that the IRG1-itaconate/Nrf2/HO-1 axis mediates oxidative stress suppression as a key mechanism by which hydrogen-rich water reduces exercise-induced fatigue.

### Mechanism

Hydrogen-rich water upregulates IRG1 expression, restoring itaconic acid levels suppressed by exercise, which in turn activates the Nrf2/HO-1 antioxidant pathway and reduces oxidative stress-driven fatigue.

## Bibliographic

- **Authors**: Zhang YJ, Ying Y, Zu X, Ding L, Shi X, Wang J, et al.
- **Journal**: Med Gas Res
- **Year**: 2026 (2026-03-01)
- **PMID**: [40580185](https://pubmed.ncbi.nlm.nih.gov/40580185/)
- **DOI**: [10.4103/mgr.MEDGASRES-D-24-00148](https://doi.org/10.4103/mgr.MEDGASRES-D-24-00148)
- **PMC**: [PMC12318582](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318582/)
- **Study type**: animal study
- **Delivery route**: hydrogen-rich water
- **Effect reported**: positive

## Delivery context

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

## Safety notes

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 40580185. https://h2-papers.org/en/papers/40580185
> **Source**: PubMed PMID [40580185](https://pubmed.ncbi.nlm.nih.gov/40580185/)