2. Academic Validation
  3. Mechanism by which hydrogen-rich water mitigates exercise-induced fatigue: activation of the immunoresponsive gene 1-itaconate/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway

Mechanism by which hydrogen-rich water mitigates exercise-induced fatigue: activation of the immunoresponsive gene 1-itaconate/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway

  • Med Gas Res. 2026 Mar 1;16(1):26-32. doi: 10.4103/mgr.MEDGASRES-D-24-00148.
Yinyin Zhang 1,  Yajing Ying 1,  Xianpeng Zu 2,  Lingling Ding 3,  Xuan Shi 4,  Jing Wang 1,  Xiangtong Li 1,  Chujian Li 1 5,  Qicheng Zhou 1,  Hui Shen 1,  Hongxia Li 1,  Hongtao Lu 1,  Jin Cheng 3
Affiliations

Affiliations

  • 1 Department of Naval Medicine, Naval Medical University, Shanghai, China.
  • 2 School of Pharmacy, Naval Medical University, Shanghai, China.
  • 3 Internal Medicine III (Nephrology and Endocrinology), Naval Medical Center, Naval Medical University, Shanghai, China.
  • 4 Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 5 College of Food Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, China.
PMID: 40580185 DOI: 10.4103/mgr.MEDGASRES-D-24-00148
Abstract

JOURNAL/mgres/04.03/01612956-202603000-00005/figure1/v/2025-06-28T140100Z/r/image-tiff Exercise-induced fatigue limits athletic performance. Molecular hydrogen is an effective treatment for relieving fatigue, but the exact mechanism is not clear. In our study, a mouse model of fatigue was established to explore the molecular mechanism by which hydrogen-rich water reduces exercise-induced fatigue. The results showed that hydrogen-rich water improved the motor function of fatigue mice, reduced the levels of fatigue-related biomarkers (blood urea nitrogen, lactate, and Creatine Kinase), and alleviated gastrocnemius muscle injury. Furthermore, ultrahigh-performance liquid chromatography-mass spectrometry revealed that hydrogen-rich water upregulated the expression of immune response gene 1 (IRG1), increased the abnormally reduced levels of itaconic acid due to fatigue, and subsequently activated the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. Finally, C2C12 cells exposed to an IRG1 inhibitor (IRG1-IN) or 4-octyl itaconic acid (4-OI) were treated with hydrogen-rich water, indicating that hydrogen-rich water effectively upregulated the expression of Nrf2 and HO-1 in cells. In summary, hydrogen-rich water alleviates exercise-induced fatigue by activating the IRG1-itaconic acid/Nrf2/HO-1 pathway and inhibiting oxidative stress.

Keywords

fatigue; heme oxygenase 1; hydrogen-rich water; immunoresponsive gene 1; itaconate; metabonomics; mitochondria; muscle; nuclear factor erythroid 2-related factor 2; oxidative stress.

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