Biological Responses to Hydrogen Molecule and its Preventive Effects on Inflammatory Diseases.

Abstract

Molecular hydrogen (H₂) was long regarded as biologically inert in multicellular organisms due to the absence of hydrogenase. Research demonstrated that H₂ inhalation substantially reduces brain damage from focal ischemia-reperfusion by counteracting oxidative stress. Although H₂ reacts with hydroxyl radicals at a rate two to three orders of magnitude lower than conventional antioxidants, it was shown to react with Fenton reaction-derived hydroxyl radicals at room temperature without a catalyst, a property exploited in ophthalmic surgery. The anti-inflammatory actions of H₂ extend beyond reactive oxygen species scavenging; H₂ administration induces mild mitochondrial oxidative stress and activates Nrf2, a phenomenon termed mitohormesis, whereby sublethal mitochondrial stress confers cellular resilience. Crosstalk between antioxidative and anti-inflammatory signaling pathways, together with immune system modulation, is proposed as the central protective mechanism. Identifying the primary biomolecular target of H₂ is highlighted as a key objective for advancing its medical applications.

Mechanism

H₂ scavenges Fenton reaction-derived hydroxyl radicals and simultaneously induces mild mitochondrial oxidative stress, activating Nrf2 via mitohormesis. Crosstalk between antioxidative and anti-inflammatory pathways, along with immune system regulation, underlies its cytoprotective effects.