# Direct Targets and Subsequent Pathways for Molecular Hydrogen to Exert Multiple Functions: Focusing on Interventions in Radical Reactions.
> 分子状水素の直接標的と多機能発現経路：ラジカル反応への介入を中心としたレビュー


## Abstract

Molecular hydrogen (H₂) was historically considered biologically inert in mammalian systems, but subsequent research established its antioxidant capacity and a broad range of additional functions, including anti-inflammatory, anti-allergic, autophagy-regulatory, and energy-metabolic effects. Because H₂ does not readily react with most biomolecules in the absence of a catalyst, identifying its direct molecular targets is critical. This review systematically examines the cascade initiated by H₂ reacting with strong oxidants such as hydroxyl radicals (•OH) in vivo. Suppression of the resulting free radical chain reaction reduces lipid peroxides and their end products; 4-hydroxy-2-nonenal derived from these peroxides upregulates the multifunctional coactivator PGC-1α. Additionally, H₂ modifies oxidized phospholipids, which may antagonize Ca²⁺-channels, thereby inactivating NFAT and CREB transcription factors—a mechanism proposed to underlie H₂ multi-functionality. Potential roles of NFAT in COVID-19, Alzheimer's disease, and advanced cancer are discussed, along with unresolved questions regarding LPS signaling, MAPK, NF-κB pathways, and the Nrf2 paradox. A novel hypothesis involving H₂-induced structural protein changes via hydration-shell alterations is also introduced.

### Mechanism

H₂ reacts with hydroxyl radicals to suppress free radical chain reactions, reducing lipid peroxides; the resulting 4-HNE upregulates PGC-1α. Separately, H₂ modifies oxidized phospholipids to antagonize Ca²⁺-channels, inactivating NFAT and CREB transcription factors and thereby mediating its diverse biological effects.

## Bibliographic

- **Authors**: Ohta S
- **Journal**: Curr Pharm Des
- **Year**: 2021
- **PMID**: [32767925](https://pubmed.ncbi.nlm.nih.gov/32767925/)
- **DOI**: [10.2174/1381612826666200806101137](https://doi.org/10.2174/1381612826666200806101137)
- **Study type**: review
- **Delivery route**: not specified
- **Effect reported**: not assessed

## Delivery context

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

## Safety notes

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices 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)

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> **Cite as**: H2 Papers — PMID 32767925. https://h2-papers.org/en/papers/32767925
> **Source**: PubMed PMID [32767925](https://pubmed.ncbi.nlm.nih.gov/32767925/)