Discovery of a hydrogen molecular target

Fe-porphyrin acts as a primary molecular target/biosensor of hydrogen (H₂), which can catalyze H₂ to reduce •OH and carbon dioxide (CO₂) into H₂O and carbon monoxide (CO), respectively, for downstream signaling.1

In 1975, Dole et al.2 found that exposure to an H₂/O₂ (97.5%:2.5%) mixed gas at a pressure of 8 atm (1 atm = 101.325 kPa) for 2 weeks caused the marked regression of skin tumors in a skin tumor-bearing mouse model, which was speculated due to the •OH and O₂^- scavenging effect of H₂. In 2007, Ohsawa et al.3 found that H₂ can selectively reduce •OH with high oxidability rather than other reactive oxygen species, but later research indicated that the probability/efficiency of the direct reduction of •OH by H₂ is considerably low.4 Increasing studies have suggested that H₂ can regulate the respiration of mitochondria,5,6,7,8,9,10 which is hardly explained by the direct •OH reduction by H₂, especially in terms of anticancer. It seems that H₂ might play a reducer or/and CO/ nitric oxide (NO)-like gasotransmitter, which was not confirmed previously with experimental evidence.

More encouragingly, Jin et al.1 experimentally identified he- matin, a kind of Fe-phorphyrins, as a molecular target/biosensor of H₂. They found that in both free and protein-confining states, Fe-porphyrin can self-catalyze hydrogenation by reacting with H₂ to obtain high reducibility of Fe-coordinated hydrogen atoms, which subsequently can not only neutralize •OH into H₂O but also reduce CO₂ into CO in the hypoxic microenvironment.

Fe-porphyrin is mainly enriched in cellular mitochondria and in red blood cells, which are the two main workplaces of H₂. At cellular mitochondria, H₂ can efficiently reduce •OH under local catalysis of Fe-porphyrin to attenuate oxidative stress for anti­inflammation. Moreover, in the hypoxia microenvironment, such as solid tumor and heart ischemia, Fe-porphyrin-catalytically generated CO is locally coordinated with Fe-porphyrin to medi­ate the downstream CO signaling, inducing apoptosis in tumor cells and protecting myocardial cells via hypoxic alleviation. The therapeutic effects on many diseases may be related to the downstream CO signaling besides •OH scavenging. Since the other medical gasses, such as NO, CO, and hydrogen sulfide (H₂S), target Fe-porphyrin (heme) to induce each signal transduction,11 it is interesting that H₂ commonly targets Fe-porphyrin (hematin) to exhibit its function.

Red blood cells containing plentiful amounts of Fe-porphyrin are a kind of natural H₂ vehicle. In the ischemia\hypoxia mi­croenvironment, red blood cells can be a local capturer of H₂ as well as a catalyst of hydrogenation for targeted H₂ therapy. In the oxygen-rich blood circulation, oxygen molecules can impede the remote delivery of hydrogen to a certain extent by exhausting reactive hydrogen, but the sufficiently hydrided red blood cells can scavenge •OH in the blood circulation and even throughout the body by virtue of rapid blood flow, which implies the neces­sity of sustainable and plentiful hydrogen supply.

In plants, the drug/drought/salt/heavy metals-tolerating and anti-oxidative stress effects of H₂12,13,14,15,16 possibly derive from downstream CO. Noticeably, a moderate H₂ concentration can maximize the therapeutic outcome of plant disease treatment, which may be due to CO poisoning at an excessively high con­centration of H₂. Therefore, an especially high dosage of H₂ will possibly cause cytotoxicity to animal cells, which can be used for anticancer and guide the exploration and avoidance of potential toxic side effects of H₂.

Some diseases such as chronic liver diseases and neurodegen­erative diseases are highly related to free Fe-porphyrin, which can induce Fenton reaction-dependent ferroptosis. The therapeutic effect of H₂ against these diseases might be owing to the intercep­tion of a Fenton-like reaction by H₂ besides catalytic scavenging of generated •OH. It can provide great inspiration for H₂-based drug discovery and development.

It is worth noting that Fe-porphyrin is identified as a hydro­genation biocatalyst that plays a role in hydrogen storage and transformation. As envisioned, transition metals-coordinated porphyrin and the molecules with a similar coordination structure are possibly valuable to hydrogen medicine/energy/agriculture for efficient hydrogen storage, safe/precision delivery, custom­ized transformation, and efficient utilization. Jin et al.1 found that hydrogen can enhance the effect of CO, and heme protein has the potential to store and transport hydrogen, which is undoubtedly an important breakthrough in the field of hydrogen biomedicine and puts forward a new direction for future research on the medical mechanism of hydrogen. However, once these effects are identi­fied, there is cause for concern that hydrogen may potentially block oxygen transport and lead to hypoxia in aerobic organisms. In any case, this may be an important advance in the study of the biological effects of hydrogen, which provides important evidence for understanding and analyzing the effects of hydrogen.

Editor note: XS and JHZ are Editorial Board members of Medical Gas Research. They were blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of these Editorial Board members and their research groups.