Oxidative Stress and Pathways of Molecular Hydrogen Effects in Medicine.

Abstract

Excessive reactive oxygen species (ROS) generated during radiation exposure, ischemia-reperfusion events, and inflammatory states damage proteins, lipids, and nucleic acids while disrupting cell signaling. Although exogenous antioxidant supplementation has been proposed as a countermeasure, clinical outcomes have generally been unfavorable. Molecular hydrogen (H₂) offers a distinct mechanistic profile: it selectively neutralizes hydroxyl radicals without eliminating ROS species required for normal cellular signaling. Beyond direct radical scavenging, H₂ modulates multiple biological processes — including inflammation, apoptosis, and autophagy — through indirect regulation of signal transduction and gene expression. Activation of the Keap1-Nrf2-ARE pathway by H₂ contributes to redox homeostasis and adaptive stress responses. Crosstalk among MAPKs, p53, NF-κB, p38 MAPK, and mTOR further accounts for the broad, pleiotropic actions observed across diverse pathological conditions. This review synthesizes current understanding of these interconnected pathways to explain the wide-ranging biological effects attributed to H₂.

Mechanism

H₂ selectively scavenges hydroxyl radicals and activates the Keap1-Nrf2-ARE pathway to restore redox balance. It also modulates apoptosis and autophagy through crosstalk involving MAPKs, p53, NF-κB, p38 MAPK, and mTOR signaling networks.