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. 2025 Aug 5;6(2):1242–1246. doi: 10.1016/j.fmre.2025.06.014

Status quo, challenges and future directions of hydrogen medicine

Shengqiang Chen 1,1, Lingting Zeng 1,1, Qianjun He 1,⁎
PMCID: PMC13069841  PMID: 41971791

Abstract

The hydrogen molecule (H2) has distinctive characteristics and advantages in broad-spectrum anti-inflammation, high biosafety and strong tissue permeability, exhibiting a therapeutic potential in numerous diseases associated with inflammation and oxidative stress. In this perspective, we attempt to show a clear picture of the status quo, challenges and future directions of hydrogen medicine in terms of biological mechanisms, metabolic behaviors, and delivery materials and techniques of H2. Firstly, we present the current understanding of biological effects and corresponding mechanisms of H2 involving the recognition of H2 molecular target, and point out the challenge of explaining the multifaceted biological behaviors of H2. Then, to explore and understand the metabolic behaviors of H2, we summarize current H2 detection techniques and identify the experimental validation of high biocarriers-crossing ability of H2 by virtue of a freshly developed H2 molecular bioprobe. Next, to develop the strategies for enhancing the efficacy of hydrogen therapy, we demonstrate the evolution of H2-delivery materials from H2 carriers to hydrolytic and catalytic H2-generating materials. Finally, we outline the future development directions of hydrogen medicine.

Keywords: Hydrogen therapy, Hydrogen medicine, Hydrogen detection, Anti-inflammation, Biomaterials, Molecular probe

1. Introduction

The hydrogen molecule (H2) had been mistakenly considered a physiologically inert gas for a long time due to its weak chemical reactivity. Till to 1975, Dole et al. [1] observed a significant regression of squamous cell carcinoma after tumor mice were treated in an environment of hydrogen/oxygen mixed gas at a pressure of 8 atmospheres for 2 weeks, suggesting that H2 has a notable biological effect. However, the high safety risk and poor operability of high-pressure hydrogen chambers, as well as the limited understanding of the anticancer mechanism of H2, resulted in the biomedical effects of H2 being overlooked for an extended period. Until 2007, Ohta et al. discovered that inhaling hydrogen gas at a low concentration of 2% could selectively scavenge highly toxic hydroxyl radicals (∙OH) within cells, leading to a substantial decrease in myocardial infarction [2]. This pivotal revelation not only further confirmed the biological effects of H2 but also ignited the burgeoning research field known as "Hydrogen Medicine".

In recent years, the advantages of hydrogen therapy have been gradually recognized, including its broad-spectrum anti-inflammatory properties, high biological safety, and strong tissue permeability. The field of hydrogen medicine has attracted extensive attention and in-depth research, resulting in a continually expanding array of findings, involving the publication of over 1500 basic research papers and 60 clinical trials [3,4]. From these publications, H2 brings definitive benefits for treating numerous inflammation/oxidative stress (OS)-related diseases such as cardiovascular diseases, cancers, arthritis, hepatitis, nephritis, pulmonitis, enteritis, gastritis, pancreatitis, dermatitis and so on. Importantly, no toxic side effects have been observed thus far. Along with research progression, multiple biological effects of H2 have been uncovered beyond selective antioxidation, including anti-inflammation, anticancer, anti-apoptosis/pro-apoptosis, pro-healing and anti-aging. However, many of the relevant mechanisms remain unclear, and some effects seem inconsistent. It is crucial to clarify the in vivo transport and metabolism behaviors of H2 to explore its therapeutic mechanisms and understand its biological characteristics. In this context, the successful development of the first H2 bioprobe enables the confirmation of the ability of H2 to swiftly traverse biological barriers, such as the blood-brain barrier (BBB), and also reveals the necessity of sustained H2 supply because of high diffusion of H2. Innovative H2-delivering materials, represented by H2 carriers, hydrolytic and catalytic H2-generating materials, have addressed the limitations of traditional H2 delivery methods, enabling localized, sustained, and high-dose H2 delivery. Despite these advancements, the efficiency of H2 delivery to the disease site still needs further enhancement. This perspective will discuss the status quo, challenges and future directions of hydrogen medicine from the view of biological mechanisms, metabolic behaviors of H2, and H2 delivery materials.

2. The biological mechanisms of H2

H2 has demonstrated therapeutic benefits based on numerous basic research studies and clinical trials, emerging as a promising therapeutic gaseous molecule with a bright application prospect. Several hypotheses about the biological mechanisms of H2 have been proposed to explain related biological effects. It is speculated that H2 can physically activate enzymes, such as acetylcholinesterase, horseradish peroxidase, and mitochondrial complex I [5], but this hypothesis encounters the challenge of explaining the reason for H2 scavenging and regulating free radicals. Extensive research has shown that H2 plays a vital role in regulating multiple signaling pathways, including ASK1, P38, MAPK, JNK, and Nrf2, to influence diverse physiological and pathological processes [3], but their target and underlying mechanisms remain elusive. Nevertheless, the viewpoint of H2 scavenging ∙OH is most widely accepted. However, one is gradually recognizing that the reducibility of H2 is so weak that the constant (4.2 × 107 M−1 s−1) of direct reaction between H2 and ∙OH is much lower than that between GSH and ∙OH (1010 M−1 s−1). Additionally, this fails to elucidate the phenomenon that H2 stimulates the generation of reactive oxygen species (ROS) in the tumor.

Inspired by hydrogenase in bacteria, it was hypothesized that there might be a specific enzyme or catalyst able to catalyze H2 to enhance its reactivity in vivo. However, this hypothesis stagnated for a period due to the absence of direct evidence. Excitingly, in 2023, we discovered that Fe-porphyrin has a hydrogenase-similar iron coordination chemical microenvironment (Fe–H/NO/CO) to serve as a molecular target/biocatalyst/biosensor of H2 (Fig. 1) [6]. Fe-porphyrin in both free and protein-confining states can self-catalyze hydrogenation by reacting with H2 to enhance the reducibility of hydrogen and accelerate its neutralization of ·OH (Fig. 1). The generation of ·OH by electron leakage in the mitochondrial electron transport chain (ETC) can be locally scavenged by H2 under the catalysis of numerous cytochromes containing Fe-porphyrin, thereby preventing the inactivation of mitochondrial ETC proteins from damage caused by electron leakage and protecting mitochondrial function [6,7]. This mediates the antioxidative, anti-inflammatory, anti-apoptotic, and anti-aging effects of H2. In the hypoxic tumor microenvironment, Fe-porphyrin can catalytically hydrogenate to reduce CO2 into CO (Fig. 1), which then mediates the CO signaling pathway in situ, inhibiting the mitochondrial respiration of tumor cells, and ultimately achieving anticancer therapy and immune regulation [6].

Fig. 1.

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The mechanisms for the molecular target of H2, and the gaps between them and the signaling pathways/multifaceted biological behaviors. Cyt, cytochrome; STEM, stem cell.

The Fe-porphyrin hypothesis initially explains the anti-oxidative, anti-cancer, anti-apoptotic, anti-inflammatory, and anti-aging effects of H2, but the mechanisms underlying the "versatile'' effects of H2 in different pathological microenvironments remain unclear. For example, in tumor treatment, H2 can activate tumor immunity, including macrophage M2-to-M1 repolarization, promote cell apoptosis and intracellular ROS generation, inhibit the proliferation and migration of tumor cells, and suppress tumor angiogenesis (Fig. 1) [8,9]. However, in the tissue repair process, H2 can inhibit the inflammatory phenotype of macrophages, activate stem cells for tissue repairing, inhibit the apoptosis of normal cells and intracellular ROS generation, promote their proliferation and migration, and enhance the angiogenesis in tissues/organs (Fig. 1) [10]. Even in the microenvironment of arthritis, H2 inhibits the inflammatory phenotype of macrophages, suppresses synovial immunity and angiogenesis, inhibits ROS production, and promotes the proliferation of chondrocytes, but inhibits the proliferation and migration of synovial cells (Fig. 1) [11,12]. The mechanisms of the "versatile" biological effects, which exhibit different cellular behaviors in different pathological environments and even within the same pathological environment among different cells, remain a complex and unresolved challenge. Additional mechanism research is urgently required to understand such complex, multifaceted biological behaviors of H2 for propelling the progression and clinical utilization of hydrogen medicine.

3. The metabolic behaviors of H2

For a long time, it has been believed that H2 has high tissue penetrability and is able to cross physiological barriers that traditional drugs cannot, owing to its small molecular size and weak polarity. However, the pharmacokinetic behavior of H2 remains unclear, primarily due to the lack of suitable hydrogen detection methods. Currently, H2 detection methods mainly include methylene blue titration, gas chromatography, and hydrogen microelectrode. Methylene blue titration is simple to operate but lacks selectivity and precision, making it suitable only for in vitro detection. Gas chromatography offers high selectivity and detection accuracy, but is complex to operate, limited to in vitro use and unable to be used for in vivo detection. In contrast, the hydrogen microelectrode method allows real-time and accurate H2 detection both in vitro and in vivo at a fixed place, but is unable to realize real-time spatial detection in vivo. Moreover, a hydrogen microelectrode is susceptible to interference from surrounding light, sound, and acidic and reductive species. Compared to traditional H2 detection methods, the development of H2 bioprobes with high selectivity and detection accuracy will enable real-time and spatial detection of H2 in vivo, which is of great significance for exploring and understanding the in vivo metabolic behavior and biological mechanisms of H2. However, the low chemical activity, high diffusivity, and low aqueous solubility of H2 pose a huge challenge for the development of H2 bioprobes with high sensitivity.

Recently, we proposed a catalytic hydrogenation strategy to develop a ratiometric fluorescent H2 bioprobe (NDI-N3/Pd@MSN, Fig. 2), realizing rapid, sensitive, and accurate detection of H2 in vivo [13]. For the first time, we directly observed the swift traversal of H2 across animal and plant barriers by utilizing this probe, confirming the robust tissue penetrability of H2 (Fig. 2). Furthermore, we also found that H2 concentrations in the brain and leaf declined rapidly after suspension of H2 gas inhalation and H2-rich water supply to the plant root [13], highlighting the rapid diffusivity of H2 and emphasizing the importance of continuous supply for sustainable treatment. We envision that the future development of H2 probes with other imaging models, such as near-infrared fluorescence, photoacoustic, magnetic resonance and Raman imaging, will be helpful in improving the spatial resolution of in vivo H2 detection (Fig. 2). Moreover, the development of small-molecule probes with low molecular weight and strong penetration will facilitate more accurate and rapid detection of H2 in the depth of tissue. It is worth noting that balancing the sensitivity and selectivity of H2 probes remains difficult. Both enhancing the catalytic hydrogenation activity of H2 probes and avoiding quenching by in vivo oxidative species pose a significant challenge.

Fig. 2.

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The structure, working principle and in vivo detection performance of the ratiometric fluorescent H2 bioprobe NDI-N3/Pd@MSN [13], and the future need for H2 bioprobes. NDI-N3/Pd@MSN, a ratiometric fluorescent H2 probe composed of Pd nanoparticles and azido-/coumarin-modified fluorophore (NDI-N3) encapsulated PEG-modified mesoporous silica nanoparticle (MSN). HRW, hydrogen-rich water.

4. The H2-delivery materials

Traditional methods for delivering H2 mainly include inhalation of hydrogen gas, drinking of hydrogen-rich water (HRW), injection of hydrogen-rich saline, and bathing with hydrogen-rich water. Direct delivery of hydrogen gas and HRW to the respiratory and digestive systems can enhance the bioavailability of H2 at the local lesion site. However, at the remote lesion site, the concentration and duration of H2 are extremely limited due to low aqueous solubility (low H2 loading capacity of water) and high diffusivity, which restricts the therapeutic efficacy of H2 to a certain extent. The emerging development of solid H2-delivery biomaterials offers new routes to the targeted, efficient, and controlled delivery of H2 to the lesion site. According to the evolution process of H2-delivery materials, we here summarize H2 carriers, hydrolytic and catalytic H2-generating materials in order.

Much different from common drug molecules, H2 is hardly loaded by general drug carriers at room temperature (RT) and normal pressure (NP) owing to its small molecular size and weak polarity. Based on the strongest H2-binding capability of Pd, Pd nanoparticles were developed as a H2 carrier to achieve rapid and effective loading of H2 at RT and NP, realizing tumor-targeted delivery and photo-controlled release of H2 as well as hydrogenothermal combined therapy for the first time (Fig. 3a) [14]. Furthermore, a nanoscale porphyrin–palladium metal–organic framework (Pd-MOF) was developed to reduce the barrier of hydrogen adsorption and increase the Pd–H coordination site (Fig. 3a), enhancing H2 loading capacity [15]. The H2 loading capacity of these carriers is higher than that of saturated HRW (1.6 μg/g) for three orders of magnitude, but it is very hard to further enhance their H2 loading efficiency [15]. On the other hand, it is worth noting that multifunctional carriers can provide supplementary therapeutic functions, such as drug loading and photothermal therapy, which can be combined with hydrogen therapy to enhance therapeutic outcomes, including the attenuation of chemotherapeutic non-specific toxicity to normal cells [16].

Fig. 3.

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Three types of H2-delivery materials and their representative characteristics: H2 carriers [14–16] (a), hydrolytic H2-generating materials [7,18] (b), and catalytic H2-generating materials (c). RT, room temperature; NP, normal pressure; MBenes, two-dimensional metal boride nanosheets; MSenes, two-dimensional metal silicide nanosheets; BPN, black phosphorus nanosheet; RPCN, red polymeric carbon nitride; NIR, near infrared light; US, ultrasound; GSH, glutathione; GSSG, oxidized glutathione; LA, lactate; PA, pyruvate; GA, gluconic acid; DFU, diabetic foot ulcer.

Furthermore, hydrolytic H2-generating materials based on metals, metal hydrides, metal borides and metal silicides have been developed to enhance H2-delivery efficiency by two orders of magnitude compared to H2 carriers (Fig. 3b). Controlling their hydrolytic H2-generating behaviors is key to maximizing the bioavailability of H2. Nanosized Fe and Fe(0)-MOF were designed to respond to weak acidity in tumors for controlled H2 release [16,17], while a base-responsive microcapsule (MgH2@EC@ES, Fig. 3b) was constructed by Eudragit S100 (ES) encapsulating MgH2 microparticles to realize intestine-targeted controlled H2 release [7]. In order to control their hydrolytic H2-generating rate, a primary battery technique was also introduced to the field of hydrogen medicine, developing various primary-battery micro-/nano-structures such as Zn-Fe and Mg@Pt [18,19]. Free heme has been identified as both a molecular target of H2 and a key inducer of some diseases such as nonalcoholic fatty liver disease, and therefore a hepatocyte-targeted delivery system (MSN-Glu) was constructed by modifying magnesium silicide nanosheets (MSN) with N-(3-triethoxysilylpropyl) gluconamide to realize liver-targeted delivery, sustained local release and molecular targeting therapy of hepatitis. This revelation underscored the correlation between H2 target and disease pathogenesis, inspiring the tailoring of targeted H2-delivery materials to realize efficient hydrogen therapy [20]. In addition, the treatment period for some chronic diseases, such as osteoarthritis and bone defects, needs several months, which cannot be met by currently existing hydrolytic H2-generating materials. Therefore, to develop materials capable of long-lasting hydrogen generation for several months will better align with the treatment window for chronic diseases to bring more benefit to the outcome of hydrogen therapy (Fig. 3b).

Compared to the above two kinds of H2 delivery materials, catalytic H2-generating materials can realize sustainable H2 generation since their substrates, such as H2O, are sufficient in the body. It is worth noting that the catalytic hydrogen generation strategy can also synergistically regulate the diseased microenvironment by oxidatively depleting the pathological microenvironment-building substrates such as glutathione (GSH) in tumor, glucose in diabetic foot ulcer (DFU) wound, polysaccharides in biofilm, lactic acid in arthritis and so on (Fig. 3c) [11,[21], [22], [23]]. For example, the photocatalytic glucose-depleting/H2-generating dressing based on TiO2:H nanorods has been approved for clinical trial for the treatment of DUF wound due to its high biosafety and therapeutic validity [21]. For deep-seated diseases, the ultrasound-mediated piezo electrocatalytic H2 generation based on some classical piezoelectric materials such as ZnS, C3N4, SnS, Bi2Te3 and Pt-Bi2S3 has been proved effective in the animal models of liver cancer and biofilm [8,9,[23], [24], [25]]. In the future, the development of catalytic H2-generating materials in response to stimuli with higher tissue penetrability such as X-ray, magnetic field and thermoelectric field will be desired but challenging because the thermoelectric/magnetoelectric/X-ray-electric conversion efficiencies of general semiconductors qualified for catalytic H2 generation with a suitable band structure are quite poor. In addition, we envision that the future development of afterglow H2-generating materials will be favorable to sustained hydrogen therapy by reducing the dependence on external stimulation.

5. Outlook

In summary, hydrogen medicine, as an emerging field, exhibits considerable potential for extensive applications. However, its development still faces many challenges, requiring collaborative efforts from researchers in multiple fields (Fig. 4). More evidences are needed to confirm the Fe-porphyrin theory, and the gap between the target and various signaling pathways must be filled. Enhancing the chemical reactivity, detection sensitivity and accuracy of the H2 probe, expanding imaging models of the H2 probe, and further tracking the in vivo metabolic behavior of H2 will be helpful to explore the biological mechanisms and understand the biological effects of H2. On this basis, imaging-guided controlled release of H2 will achieve the integration of diagnosis and treatment of major diseases. Currently, the dosage, frequency and administration route of hydrogen therapy have not been standardized, resulting in reduced comparability of various results. The dosage–efficacy relationship for hydrogen therapy in treating various diseases is clear, but the long-term side effects of H2 at high concentrations remain unclear. H2-delivery materials can achieve targeted, timed, and quantitative delivery, which is conducive to establishing standard treatment protocols for hydrogen medicine and improving the feasibility of clinical application. In addition, most hydrogen medicine research remains at the stage of animal experiments and small-scale clinical trials. Large-scale, multi-center, randomized double-blinded controlled clinical trials for hydrogen therapy of many diseases are urgently needed to further verify the validity and safety of H2 and to provide more solid evidence for its clinical translation. Hydrogen medicine will be very helpful to the treatment of major refractory inflammation-related diseases in the future.

Fig. 4.

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The summary and outlook of hydrogen medicine.

Declaration of competing interest

The authors declare that they have no conflicts of interest in this work.

Acknowledgments

The work was supported by the National Natural Science Foundation of China (52425309, U23A20690, 82172078) and the National Key Research and Development Program of China (2022YFB3804500).

Biographies

Shengqiang Chen received his master's degree from the School of Biomedical Engineering, Shenzhen University, in June 2023. Currently, he is conducting a PhD program at the School of Materials Science and Engineering, Shanghai Jiao Tong University. His main research interests focus on the development, application and clinical transformation of H2 delivery biomaterials, especially in the field of tissue engineering.

Lingting Zeng received her master's degree from the School of Biomedical Engineering, Shenzhen University, in June 2022. She is currently conducting a PhD program at the School of Materials Science and Engineering, Shanghai Jiao Tong University. Her main research interests involve the development and clinical transformation of H2-delivering biomaterials, especially catalytic H2-generating nanomaterials.

Qianjun He (BRID: 09953.00.52833) is a winner of the Distinguished Young Scholars of the National Natural Science Foundation of China, and a Tenured Professor at Shanghai Jiao Tong University (SJTU). He was awarded Distinguished Leadership in Molecular Hydrogen Research by the European Academy for Molecular Hydrogen Research in Biomedicine. He is now the vice-chair of the International Society for Hydrogen Medicine and Hydrogen Biology. His research focuses on the engineering and development of advanced nanomaterials and nanomedicines for precision theranostics and hydrogen therapy of major diseases.

Footnotes

Peer review under the responsibility of Editorial Board of Fundamental Research.

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