Paradigm shift in hydrogen medicine: Target molecules and catalytic mechanisms elucidated at the atomic level.

Molecular hydrogen (H2) has been shown to exert antioxidant and anti-inflammatory effects across a broad spectrum of disease models and clinical trials; however, its direct reaction rate with hydroxyl radicals (•OH) in aqueous solution is exceedingly slow, and the underlying mechanism of action has remained unresolved for many years as the "hydrogen paradox". The present review delineates a paradigm shift that resolves this enigma from three distinct perspectives. First, oxidized Fe-porphyrin "hematin [Fe(III)-OH]" has been identified as a redox-related biosensor for H2, reducing •OH selectively to water through a catalytic cycle. Ab initio density functional theory calculations support the notion that H2 does not interfere with normal ferrous heme, but intervenes exclusively in pathologically hyperoxidized heme. Second, we propose a novel mechanism whereby H2 performs one-electron reduction of the high-valent ferryl iron intermediate Compound I [Fe(IV) = O·P•+] of myeloperoxidase during neutrophil extracellular trap formation, selectively arresting hypochlorous acid production and immunothrombosis without compromising normal bactericidal function. Third, we discuss how the identical concept of "high-valent iron overheat protection" applies to mitochondrial Complex IV, potentially explaining the maintenance of aerobic energy metabolism and the suppression of lactate accumulation. We present a unified paradigm shift in which H2 functions as the ultimate biological fail-safe mechanism, exerting pinpoint control exclusively over the pathological "runaway oxygen engine" driven by oxidative stress, while leaving normal enzymatic activity entirely intact.