There are many situations of excessive production of reactive oxygen species (ROS) such as radiation,
ischemia/reperfusion (I/R), and inflammation. ROS contribute to and arises from numerous cellular pathologies,
diseases, and aging. ROS can cause direct deleterious effects by damaging proteins, lipids, and nucleic acids as
well as exert detrimental effects on several cell signaling pathways. However, ROS are important in many cellular
functions. The injurious effect of excessive ROS can hypothetically be mitigated by exogenous antioxidants, but
clinically this intervention is often not favorable. In contrast, molecular hydrogen provides a variety of advantages
for mitigating oxidative stress due to its unique physical and chemical properties. H2 may be superior to
conventional antioxidants, since it can selectively reduce ●OH radicals while preserving important ROS that are
otherwise used for normal cellular signaling. Additionally, H2 exerts many biological effects, including antioxidation,
anti-inflammation, anti-apoptosis, and anti-shock. H2 accomplishes these effects by indirectly regulating
signal transduction and gene expression, each of which involves multiple signaling pathways and crosstalk.
The Keap1-Nrf2-ARE signaling pathway, which can be activated by H2, plays a critical role in regulating cellular
redox balance, metabolism, and inducing adaptive responses against cellular stress. H2 also influences the crosstalk
among the regulatory mechanisms of autophagy and apoptosis, which involve MAPKs, p53, Nrf2, NF-κB,
p38 MAPK, mTOR, etc. The pleiotropic effects of molecular hydrogen on various proteins, molecules and signaling
pathways can at least partly explain its almost universal pluripotent therapeutic potential.