Submitted:
20 March 2025
Posted:
20 March 2025
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Abstract
Keywords:
1. Biological Characteristics of Molecular Hydrogen
1.1. Hydrogen Selective Antioxidant
1.2. Research on the Anti-Inflammatory Mechanism of Hydrogen Gas
1.3. Regulatory Functions of Hydrogen Signaling
1.4. The Protective Effect of Hydrogen on Mitochondria
2. The Impact of Hydrogen on Tumors
2.1. Inhibit Tumor Cell Proliferation
2.2. Inducing Apoptosis of Tumor Cells
2.3. Interference with Tumor Metabolic Pathways
3. Exploration of Molecular Hydrogen Drug Delivery Technology
4. Molecular Hydrogen Combined with Other Therapies
4.1. Research Progress on Combined Radiotherapy
4.2. Observation of the Effect of Combined Chemotherapy
4.3. Immunotherapeutic Synergy
5. Future Perspectives in Hydrogen Therapy
6. Conclusion
Author Contributions
Conflict of interest disclosure
Funding
References
- Bray, F.; Laversanne, M.; Sung, H.; et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 2024, 74, 229–263. [Google Scholar] [CrossRef]
- Siegel, R.L.; Giaquinto, A.N.; Jemal, A. Cancer statistics, 2024. CA: a cancer journal for clinicians 2024, 74, 12–49. [Google Scholar] [CrossRef]
- Zhou, W.; Zhang, J.; Chen, W.; et al. Prospects of molecular hydrogen in cancer prevention and treatment. Journal of Cancer Research and Clinical Oncology 2024, 150, 170. [Google Scholar] [CrossRef]
- Hirano, S.; Ichikawa, Y.; Sato, B.; et al. Molecular hydrogen as a potential clinically applicable radioprotective agent. International journal of molecular sciences 2021, 22, 4566. [Google Scholar] [CrossRef]
- Yamamoto, H.; Ichikawa, Y.; Hirano, S.; et al. Molecular hydrogen as a novel protective agent against pre-symptomatic diseases. International Journal of Molecular Sciences 2021, 22, 7211. [Google Scholar] [CrossRef]
- Herb, M.; Schramm, M. Functions of ROS in macrophages and antimicrobial immunity. Antioxidants 2021, 10, 313. [Google Scholar] [CrossRef]
- Cheung, E.C.; Vousden, K.H. The role of ROS in tumour development and progression. Nature Reviews Cancer 2022, 22, 280–297. [Google Scholar] [CrossRef]
- Sahoo, B.M.; Banik, B.K.; Borah, P.; et al. Reactive oxygen species (ROS): key components in cancer therapies. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents) 2022, 22, 215–222. [Google Scholar] [CrossRef]
- Ohsawa, I.; Ishikawa, M.; Takahashi, K.; et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature medicine 2007, 13, 688–694. [Google Scholar] [CrossRef] [PubMed]
- Ohta, S. Direct targets and subsequent pathways for molecular hydrogen to exert multiple functions: focusing on interventions in radical reactions. Current Pharmaceutical Design 2021, 27, 595–609. [Google Scholar] [CrossRef] [PubMed]
- Wu, C.; Zou, P.; Feng, S.; et al. Molecular hydrogen: an emerging therapeutic medical gas for brain disorders. Molecular neurobiology 2023, 60, 1749–1765. [Google Scholar] [CrossRef] [PubMed]
- Li, H.; Sun, H.; Li, S.; et al. Hydrogen alleviates hypoxic–ischaemic brain damage in neonatal rats by inhibiting injury of brain pericytes. Journal of Cellular and Molecular Medicine 2024, 28, e18505. [Google Scholar] [CrossRef] [PubMed]
- Qian, L.; Shen, J.; Chuai, Y.; et al. Hydrogen as a new class of radioprotective agent. International journal of biological sciences 2013, 9, 887. [Google Scholar] [CrossRef]
- Kura, B.; Kalocayova, B.; LeBaron, T.W.; et al. Regulation of microRNAs by molecular hydrogen contributes to the prevention of radiation-induced damage in the rat myocardium. Molecular and Cellular Biochemistry 2019, 457, 61–72. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Liu, P.Y.; Bao, W.; et al. Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway. BMC cancer 2020, 20, 1–19. [Google Scholar] [CrossRef]
- Liu, M.; Xie, F.; Zhang, Y.; et al. Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation. Stem Cell Research & Therapy 2019, 10, 1–10. [Google Scholar]
- Adzavon, Y.M.; Xie, F.; Yi, Y.; et al. Long-term and daily use of molecular hydrogen induces reprogramming of liver metabolism in rats by modulating NADP/NADPH redox pathways. Scientific reports 2022, 12, 3904. [Google Scholar] [CrossRef] [PubMed]
- Balkwill, F.; Mantovani, A. Inflammation and cancer: back to Virchow? The lancet 2001, 357, 539–545. [Google Scholar] [CrossRef]
- Greten, F.R.; Grivennikov, S.I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 2019, 51, 27–41. [Google Scholar] [CrossRef]
- Du, J.; Li, J.; Li, R.; et al. High concentration of hydrogen ameliorates lipopolysaccharide-induced acute lung injury in a sirt1-dependent manner. Respiratory Physiology & Neurobiology 2022, 296, 103808. [Google Scholar]
- Sun, R.; Zhao, N.; Wang, Y.; et al. High concentration of hydrogen gas alleviates Lipopolysaccharide-induced lung injury via activating Nrf2 signaling pathway in mice. International immunopharmacology 2021, 101, 108198. [Google Scholar] [CrossRef] [PubMed]
- Peng, J.; He, Q.; Li, S.; et al. Hydrogen-rich water mitigates LPS-induced chronic intestinal inflammatory response in rats via Nrf-2 and NF-κB signaling pathways. Veterinary Sciences 2022, 9, 621. [Google Scholar] [CrossRef] [PubMed]
- Yang, C.; He, Y.; Ren, S.; et al. Hydrogen Attenuates Cognitive Impairment in Rat Models of Vascular Dementia by Inhibiting Oxidative Stress and NLRP3 Inflammasome Activation. Advanced Healthcare Materials 2024, 13, 2400400. [Google Scholar] [CrossRef]
- Matsuura, H.; Matsumoto, H.; Okuzaki, D.; et al. Hydrogen gas therapy attenuates inflammatory pathway signaling in septic mice. Journal of Surgical Research 2021, 263, 63–70. [Google Scholar] [CrossRef]
- Murray, P.J.; Allen, J.E.; Biswas, S.K.; et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014, 41, 14–20. [Google Scholar] [CrossRef]
- Boutilier, A.J.; Elsawa, S.F. Macrophage polarization states in the tumor microenvironment. International journal of molecular sciences 2021, 22, 6995. [Google Scholar] [CrossRef] [PubMed]
- Shi, J.H.; Liu, L.N.; Song, D.D.; et al. TRAF3/STAT6 axis regulates macrophage polarization and tumor progression. Cell Death & Differentiation 2023, 30, 2005–2016. [Google Scholar]
- Locati, M.; Curtale, G.; Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annual Review of Pathology: Mechanisms of Disease 2020, 15, 123–147. [Google Scholar] [CrossRef]
- Gao, X.; Niu, S.; Li, L.; et al. Hydrogen therapy promotes macrophage polarization to the M2 subtype in radiation lung injury by inhibiting the NF-κB signalling pathway. Heliyon 2024, 10, e30902. [Google Scholar] [CrossRef]
- Su, J.; Zhang, Y.; Cheng, C.; et al. Hydrogen regulates the M1/M2 polarization of alveolar macrophages in a rat model of chronic obstructive pulmonary disease. Experimental Lung Research 2021, 47, 301–310. [Google Scholar] [CrossRef]
- Wei, Y.; Wang, K.; Zhang, Y.; et al. Potent anti-inflammatory responses: Role of hydrogen in IL-1α dominated early phase systemic inflammation. Frontiers in Pharmacology 2023, 14, 1138762. [Google Scholar] [CrossRef] [PubMed]
- Yin, H.; Feng, Y.; Duan, Y.; et al. Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response in mice. Journal of Inflammation 2022, 19, 16. [Google Scholar] [CrossRef] [PubMed]
- Guo, L.; Liu, M.; Duan, T. Hydrogen suppresses oxidative stress by inhibiting the p38 MAPK signaling pathway in preeclampsia. Advances in Clinical and Experimental Medicine 2023, 32, 357–367. [Google Scholar] [CrossRef] [PubMed]
- Geng, N.; Gao, X.; Wang, X.; et al. Hydrogen helps to ameliorate Staphylococcus aureus-induced mastitis in mice. International Immunopharmacology 2022, 109, 108940. [Google Scholar] [CrossRef]
- Zhang, X.; Tao, G.; Zhao, Y.; et al. Molecular hydrogen inhibits colorectal cancer growth via the AKT/SCD1 signaling pathway. BioMed Research International 2022, 2022, 8024452. [Google Scholar] [CrossRef]
- Jiang, Y.; Liu, G.; Zhang, L.; et al. Therapeutic efficacy of hydrogen-rich saline alone and in combination with PI3K inhibitor in non-small cell lung cancer. Molecular Medicine Reports 2018, 18, 2182–2190. [Google Scholar] [CrossRef]
- Hu, Y.; Wang, P.; Han, K. Hydrogen attenuated inflammation response and oxidative in hypoxic ischemic encephalopathy via Nrf2 mediated the inhibition of NLRP3 and NF-κB. Neuroscience 2022, 485, 23–36. [Google Scholar] [CrossRef]
- Diao, M.; Zhang, S.; Wu, L.; et al. Hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury via the Nrf2 pathway in rabbits. Inflammation 2016, 39, 2029–2039. [Google Scholar] [CrossRef]
- Sumbalová, Z.; Kucharská, J.; Rausová, Z.; et al. The effect of adjuvant therapy with molecular hydrogen on endogenous coenzyme Q10 levels and platelet mitochondrial bioenergetics in patients with non-alcoholic fatty liver disease. International Journal of Molecular Sciences 2023, 24, 12477. [Google Scholar] [CrossRef]
- Akagi, J.; Baba, H. Hydrogen gas activates coenzyme Q10 to restore exhausted CD8+ T cells, especially PD-1+ Tim3+ terminal CD8+ T cells, leading to better nivolumab outcomes in patients with lung cancer. Oncology Letters 2020, 20, 258. [Google Scholar] [CrossRef]
- Qiu, X.; Dong, K.; Guan, J.; et al. Hydrogen attenuates radiation-induced intestinal damage by reducing oxidative stress and inflammatory response. International immunopharmacology 2020, 84, 106517. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Wang, L.; Zhang, Y.; et al. Hydrogen gas inhibits lung cancer progression through targeting SMC3. Biomedicine & pharmacotherapy 2018, 104, 788–797. [Google Scholar]
- Hu, P.; Lin, L.; Chen, G.; et al. Hydrogen-Generating Magnesium Alloy Seed Strand Sensitizes Solid Tumors to Iodine-125 Brachytherapy. Advanced Science 2025, 12, 2412263. [Google Scholar] [CrossRef] [PubMed]
- Yang, N.; Gong, F.; Liu, B.; et al. Magnesium galvanic cells produce hydrogen and modulate the tumor microenvironment to inhibit cancer growth. Nature Communications 2022, 13, 2336. [Google Scholar] [CrossRef]
- Zan, R.; Wang, H.; Cai, W.; et al. Controlled release of hydrogen by implantation of magnesium induces P53-mediated tumor cells apoptosis. Bioactive materials 2022, 9, 385–396. [Google Scholar] [CrossRef] [PubMed]
- Zhu, B.; Cui, H.; Xu, W. Hydrogen inhibits the proliferation and migration of gastric cancer cells by modulating lncRNA MALAT1/miR-124-3p/EZH2 axis. Cancer Cell International 2021, 21, 1–10. [Google Scholar] [CrossRef]
- Saitoh, Y.; Kawasaki, N.; Eguchi, N.; et al. Combined treatment with dissolved hydrogen molecule and platinum nanocolloid exerts carcinostatic/carcinocidal effects by increasing hydrogen peroxide generation and cell death in the human gastric cancer cell line NUGC-4. Free Radical Research 2021, 55, 211–220. [Google Scholar] [CrossRef]
- Li, Q.; Tanaka, Y.; Miwa, N. Influence of hydrogen-occluding-silica on migration and apoptosis in human esophageal cells in vitro. Medical Gas Research 2017, 7, 76–85. [Google Scholar]
- Chu, J.; Gao, J.; Wang, J.; et al. Mechanism of hydrogen on cervical cancer suppression revealed by high-throughput RNA sequencing. Oncology reports 2021, 46, 141. [Google Scholar] [CrossRef]
- Zhang, Y.; Chen, G.; Yan, Z.; et al. Hydrogen gas promotes apoptosis of lung adenocarcinoma A549 cells through X-linked inhibitor of apoptosis and baculoviral inhibitor of apoptosis protein repeat-containing 3. Journal of Cancer Research and Therapeutics 2022, 18, 1380–1386. [Google Scholar] [CrossRef]
- Wu, Y.; Su, L.; Yuan, M.; et al. In vivo X-ray triggered catalysis of H2 generation for cancer synergistic gas radiotherapy. Angewandte Chemie 2021, 133, 12978–12985. [Google Scholar] [CrossRef]
- Barba, I.; Carrillo-Bosch, L.; Seoane, J. Targeting the Warburg effect in cancer: where do we stand? International Journal of Molecular Sciences 2024, 25, 3142. [Google Scholar] [CrossRef] [PubMed]
- Niu, Y.; Nie, Q.; Dong, L.; et al. Hydrogen attenuates allergic inflammation by reversing energy metabolic pathway switch. Scientific Reports 2020, 10, 1962. [Google Scholar] [CrossRef]
- Iketani, M.; Sakane, I.; Fujita, Y.; et al. H2-induced transient upregulation of phospholipids with suppression of energy metabolism. Medical Gas Research 2023, 13, 133–141. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.C. Inhibitory effect of hydrogen on the progression of non-small cell lung cancer and its mechanism exploration. Hebei Medical University, 2019. [Google Scholar]
- Yan, Z.F. Study on hydrogen-induced apoptosis promotion and proliferation inhibition in lung adenocarcinoma A549 cells. Hebei Medical University, 2019. [Google Scholar]
- Chen, J.B.; Kong, X.F.; Mu, F.; et al. Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer. Medical Gas Research 2020, 10, 75–80. [Google Scholar] [PubMed]
- Asgharzadeh, F.; Tarnava, A.; Mostafapour, A.; et al. Hydrogen-rich water exerts anti-tumor effects comparable to 5-fluorouracil in a colorectal cancer xenograft model. World Journal of Gastrointestinal Oncology 2022, 14, 242. [Google Scholar] [CrossRef]
- Yamasaki, M.; Miyazono, M.; Yoshihara, M.; et al. Effects of hydrogen-rich water in a rat model of polycystic kidney disease. Plos one 2019, 14, e0215766. [Google Scholar] [CrossRef]
- Lian, N.Q. Hydrogen-rich water modulates gut microbiota in chemotherapy-induced pathological neuropathic pain. Tianjin Medical University, 2021. [Google Scholar]
- Toshkova, R.; Neshev, N.; Ignatov, I.; et al. Effects of hydrogen-rich water on hamsters with experimental myeloid tumor. Libri Oncologici: Croatian Journal of Oncology 2023, 51, 85–96. [Google Scholar] [CrossRef]
- Hu, N.; Zhao, H.W.; Zhang, X.B.; et al. Effects and mechanisms of hydrogen-rich solution on chemotherapy-induced cognitive dysfunction in mice. Shandong Medical Journal 2019, 59, 13–17. [Google Scholar]
- Chen, Y.L. Preliminary study on preventive effects of hydrogen-rich solution against radioactive osteonecrosis of jaw. Fourth Military Medical University, 2017. [Google Scholar]
- Tanaka, Y.; Xiao, L.; Miwa, N. Hydrogen-rich bath with nano-sized bubbles improves antioxidant capacity based on oxygen radical absorbing and inflammation levels in human serum. Medical Gas Research 2022, 12, 91–99. [Google Scholar] [CrossRef]
- Asada, R.; Saitoh, Y.; Miwa, N. Effects of hydrogen-rich water bath on visceral fat and skin blotch, with boiling-resistant hydrogen bubbles. Medical Gas Research 2019, 9, 68–73. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Q.; Wu, Y.; Li, Y.; et al. Positive effects of hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques. Scientific Reports 2018, 8, 8051. [Google Scholar] [CrossRef] [PubMed]
- Noda, K.; Shigemura, N.; Tanaka, Y.; et al. A novel method of preserving cardiac grafts using a hydrogen-rich water bath. The Journal of Heart and Lung Transplantation 2013, 32, 241–250. [Google Scholar] [CrossRef] [PubMed]
- Kang, K.M.; Kang, Y.N.; Choi, I.B.; et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Medical gas research 2011, 1, 1–8. [Google Scholar] [CrossRef]
- Kalman, N.S.; Zhao, S.S.; Anscher, M.S.; et al. Current status of targeted radioprotection and radiation injury mitigation and treatment agents: a critical review of the literature. International Journal of Radiation Oncology* Biology* Physics 2017, 98, 662–682. [Google Scholar] [CrossRef]
- Kuo, D.Y.; Wang, Y.C.; Chou, P.H.; et al. Therapeutic Potential of Hydrogen as a Radioprotective Agent for the Prevention of Radiation Dermatitis. Antioxidants 2024, 13, 1475. [Google Scholar] [CrossRef]
- Crawford, J.; Dale, D.C.; Lyman, G.H. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 2004, 100, 228–237. [Google Scholar] [CrossRef]
- Donati, F.; Cioni, D.; Guarino, S.; et al. Chemotherapy-induced liver injury in patients with colorectal liver metastases: findings from MR imaging. Diagnostics 2022, 12, 867. [Google Scholar] [CrossRef]
- Bosnjak, S.M.; Zilic, A.; Radhakrishnan, V.; et al. MASCC antiemetic consensus recommendations: resource-limited settings. Supportive Care in Cancer 2025, 33, 181. [Google Scholar] [CrossRef]
- Chen, J.B.; Kong, X.F.; Lv, Y.Y.; et al. “Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients. Medical Gas Research 2019, 9, 115–121. [Google Scholar]
- Postow, M.A.; Sidlow, R.; Hellmann, M.D. Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine 2018, 378, 158–168. [Google Scholar] [CrossRef] [PubMed]
- Yan, H.; Fan, M.; Liu, H.; et al. Microbial hydrogen “manufactory” for enhanced gas therapy and self-activated immunotherapy via reduced immune escape. Journal of Nanobiotechnology 2022, 20, 280. [Google Scholar] [CrossRef] [PubMed]
- Meng, X.; Liu, Z.; Deng, L.; et al. Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity. Advanced Science 2024, 11, 2401269. [Google Scholar] [CrossRef]
- Li, J.; Wang, G.; Wen, Z.; et al. Modulating the Electronic Structure of MnNi2S3 Nanoelectrodes to Activate Pyroptosis for Electrocatalytic Hydrogen-Immunotherapy. Advanced Materials 2024, 36, 2412925. [Google Scholar] [CrossRef] [PubMed]
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