Hydrogen molecule (H₂) exhibits broad-spectrum but microenvironment-dependent biomedical effects in varied oxidation stress-related diseases, but its molecular mechanism is unclear and its targeting molecule is unknown so far. Herein, we originally reveal that Fe-porphyrin is a H₂-targeted molecule. We have demonstrated that the oxidized Fe-porphyrin in both free and protein-confining states can self-catalyze the hydrogenation/reduction by reacting with H₂ to catalytically scavenge ∙OH, and can also catalytically hydrogenate to reduce CO₂ into CO in the hypoxic microenvironment of in vitro simulation and in vivo tumor, confirming that Fe-porphyrin is a redox-related biosensor of H₂ and H₂ is an upstream signaling molecule of CO. These discoveries are favorable for deep understanding and exploration of profound biomedical effects of H₂, and helpful for development of innovative drugs and hydrogen energy/agricultural materials.