Direct Targets and Subsequent Pathways for Molecular Hydrogen to Exert Multiple Functions: Focusing on Interventions in Radical Reactions.

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.