Molecular Hydrogen in Health and Medicine
Molecular hydrogen (H₂) is a diatomic gas that, in biological systems, functions as a selective antioxidant preferentially neutralizing the most cytotoxic reactive oxygen species while preserving physiologically important radicals involved in normal cell signaling[^c1][^c2]. This selectivity distinguishes it from conventional antioxidants and has made it the subject of extensive biomedical research since the landmark 2007 study by Ohsawa et al. in Nature Medicine[^c3]. Beyond direct radical scavenging, H₂ activates the Nrf2 transcription factor to upregulate endogenous antioxidant enzymes, inhibits the NF-κB pathway to reduce pro-inflammatory cytokines, and protects mitochondrial function[^c4][^c5]. By mid-2026, over 1,500 basic research papers and 60 clinical trials had been published on hydrogen medicine[^c29], and the 12th China Hydrogen Biomedicine Conference (July 2026, Harbin) featured 9 keynote and 16 topical presentations spanning cardiovascular, neurological, respiratory, and metabolic applications, reflecting the field's ongoing expansion toward clinical translation[^c64].
The mechanistic understanding of molecular hydrogen underwent a paradigm shift in 2026. A major review established that H₂'s biological effects cannot be fully explained by direct radical scavenging alone — the "stoichiometric mismatch" between H₂'s micromolar in vivo concentration and the magnitude of its biological effects prompted a conceptual move from a framework of "passive free radical scavenging" to "active regulation of the redox–mitochondria–metabolism network"[^c32]. Key advances include the identification of the Nrf2/PINK1/Parkin-mediated mitophagy pathway as a central mechanism of H₂ neuroprotection[^c33], the discovery that H₂ inhibits ferroptosis via the Nrf2/GPX4/HO-1 pathway in cerebral ischemia-reperfusion injury[^c38], the recognition that H₂ coordinates mitochondrial biogenesis, dynamics, and mitophagy through the AMPK/Sirtuins/PGC-1α signaling axis[^c32], and the demonstration that H₂ inhalation reduces hippocampal ROS, Aβ42 accumulation, and neuroinflammation in the 5xFAD Alzheimer's mouse model[^c34]. The Rieske iron–sulfur protein (RISP) in mitochondrial complex III was identified as a primary molecular target, triggering a mitohormetic adaptive response through the mitochondrial unfolded protein response[^c13]. In 2023–2024, Fe-porphyrin (heme) was identified as an additional core molecular target, providing a unified explanation for H₂'s selective antioxidant mechanism[^c22]. In 2026, a novel anti-inflammatory mechanism was discovered in which H₂ promotes PKM2 lactylation to block NLRP3 inflammasome activation and pyroptosis in ulcerative colitis[^c61]. In sepsis-associated encephalopathy, a 2026 study identified SIRT1-mediated regulation of PINK1-dependent mitophagy as a core mechanism through which H₂ attenuates neuroinflammation and neuronal apoptosis[^c51], and a second 2026 study identified ATG9B as the most significantly upregulated mitophagy-related gene in response to H₂, establishing ATG9B-mediated mitophagy as a complementary neuroprotective pathway[^c56]. A 2026 study further consolidated the multi-pathway mechanism by demonstrating that H₂ activates the Nrf2/HO-1 pathway to alleviate cognitive impairment from chronic sleep deprivation[^c67]. A 2026 review further consolidated the multi-pathway mechanism of hydrogen-rich water, demonstrating that HRW activates Nrf2/ARE pathways, suppresses NF-κB and MAPK inflammatory cascades, and modulates JAK/STAT signaling[^c59]. A 2025 Monte Carlo simulation study provided quantitative validation of H₂'s selective hydroxyl radical scavenging mechanism in a radiation-chemical context[^c72].
The biological effects of H₂ have been investigated across more than 38 disease conditions, including ischemia-reperfusion injury, neurodegenerative disorders, cardiovascular disease, metabolic syndrome, and inflammatory conditions[^c6]. Clinical research in 2026 continued to expand across multiple therapeutic areas. A comprehensive review by Professor Sun Xuejun mapped hydrogen therapy onto the American Heart Association's "Life's Essential 8" framework for cardiovascular health, concluding that up to seven of the eight metrics — diet, exercise, smoking, sleep, weight, blood lipids, blood glucose, and blood pressure — can be positively influenced by hydrogen intervention[^c65]. In cardiovascular medicine, a pioneering injectable hydrogel encapsulating living photosynthetic bacteria that produces H₂ on demand when exposed to light demonstrated reduced infarct size and improved cardiac function after myocardial ischemia-reperfusion injury in rodent and porcine models[^c28]. A registered clinical trial (NCT07085637) investigated intravenous hydrogen nanobubbles as a novel administration route, evaluating cardiovascular function and quality of life across escalating doses from 5 to 25 mL in healthy adults[^c82]. A 2026 study demonstrated that molecular hydrogen mitigates cardiac ferroptosis induced by chronic intermittent hypoxia, a model of obstructive sleep apnea, through Nrf2 activation and promotion of autophagy[^c57]. The first systematic review on H₂ in heart failure models, published November 2025, concluded that H₂ reduces cardiac oxidative stress, inflammation, and cardiomyocyte death while improving mitochondrial function and attenuating cardiac remodeling across multiple HF subtypes[^c49]. A 2026 study demonstrated that hydrogen-rich water attenuates atherosclerosis in ApoE⁻/⁻ mice by modulating the gut microbiota-propionate-macrophage axis[^c50]. A head-to-head preclinical comparison of H₂-rich water versus 4% H₂ inhalation in radiation-induced heart disease showed both routes effectively decreased oxidative stress and normalized the Nrf2/Keap1 pathway, with a trend favoring inhalation[^c36]. In sports medicine, a randomized controlled trial of alkaline hydrogen-rich water in 40 physically active adults demonstrated a significant reduction in post-exercise IL-6 levels, with a large effect size, and stable malondialdehyde levels compared to controls[^c35], and a major European clinical trial at Gdańsk University of Physical Education and Sport began investigating the effects of daily H₂ inhalation on BDNF, iron metabolism, gene expression, and serum anti-tumor potential[^c68]. Low-concentration hydrogen inhalation improved cognitive function in elderly women with mild cognitive impairment, shifting MMSE scores from the suspected dementia range to the normal range[^c18]. In metabolic research, a 2026 study introduced hydrogen-rich jelly as a novel gel-based delivery format and demonstrated that it suppressed adipose tissue inflammation, restored adiponectin levels, and partially improved glucose tolerance in a mouse model of accelerated aging with metabolic stress[^c58]. A closed-loop glucose-responsive wound dressing combining nitric oxide and molecular hydrogen demonstrated complete wound closure in diabetic mouse models[^c20]. A 2026 multimodal nanoplatform (CO/AB@MPDA) combining photothermal therapy with CO and H₂ gas therapy demonstrated synergistic antibacterial and wound-healing effects in diabetic infected wounds[^c77]. The first Phase III multicenter randomized controlled trial of supersaturated hydrogen-rich water for weight management (the HOPE trial) began recruitment in April 2026[^c14]. A 2024 meta-analysis of eight double-blind randomized trials in 357 patients with metabolic disorders found that hydrogen-rich water produced slight, mostly non-significant reductions across lipid parameters[^c87]. In geriatric health, a 2026 prospective observational study in 48 community-dwelling older adults found that routine hydrogen-rich water consumption was associated with significantly greater improvement in chair stand test performance and gait speed over six months[^c62]. A 2025 comprehensive review proposed that nanoplatform-based delivery systems could address current challenges in targeted H₂ delivery, and highlighted interactions between hydrogen and gut microbiota as a promising area for mechanistic research[^c73].
In autoimmune disease, two 2026 case reports provided important clinical evidence for H₂ in systemic lupus erythematosus. A 43-year-old woman with SLE and recurrent infections from high-dose immunosuppression achieved complete discontinuation of mycophenolic acid within one month of adjunctive H₂ capsule therapy, with anti-dsDNA levels stabilizing below 15 IU/mL and durable remission through early 2026[^c80]. A second case described a 27-year-old woman with refractory malar rash who showed sustained improvement after H₂ capsule therapy, with reductions in ANA and anti-dsDNA antibody levels and modulation of T-cell and B-cell markers[^c81]. These cases contribute to a growing body of evidence suggesting H₂ as a potential immunomodulatory adjunct in SLE. A 2025 randomized controlled trial in elite female athletes demonstrated that hydrogen-rich water consumption increased muscle mass, reduced fat mass, and improved maximal torque while decreasing markers of muscle damage[^c19].
In neurological applications, two randomized controlled trials demonstrated that prophylactic hydrogen inhalation reduced the incidence of postoperative delirium in elderly surgical patients. A 2018 study in 80 hip fracture patients reported a reduction from 30% to 7.5%[^c69], and a 2022 trial in 184 noncardiac surgery patients found a reduction from 24% to 12%[^c70], both mediated by anti-inflammatory mechanisms. These findings add to the growing body of perioperative hydrogen research, which also includes a glioma trial showing reduced brain edema and improved sleep[^c3]. In Parkinsonism, the first clinical trial of intravenous hydrogen nanobubble injection was inaugurated at Universitas Brawijaya Hospital in September 2024, targeting 35 patients over one year, with preliminary findings from the first six patients showing improved cognitive function and quality of life[^c78][^c79]; the trial is formally registered with the WHO as a single-group, open-label Phase 2/Phase 3 study (NCT07466381), whose recruitment status is recorded as Completed[^c92][^c93]. A 2022 pilot study of 200 Chinese patients with acute cerebral infarction found that inhalation of 3% hydrogen gas produced significantly greater improvement in neurological scores, with faster onset and improved MRI recovery, than standard therapy[^c88][^c89]. In oncology, a 2026 pilot randomized controlled trial in 20 patients with locally advanced head and neck cancer found that adjunctive H₂ inhalation during concurrent chemoradiotherapy was associated with numerically lower frequencies of moderate treatment-related toxicities and fewer chemotherapy delays[^c76].
A landmark 2025 study in Nature Microbiology identified the group B [FeFe]-hydrogenase as the primary driver of fermentative H₂ production in the healthy human gut, with Bacteroides species as major producers. This enzyme was shown to be significantly depleted in Crohn's disease patients, who exhibited a restructured gut hydrogen economy[^c37]. In dermatology, a 2026 study demonstrated that hydrogen-rich water inhibits the cGAS-STING signaling pathway in psoriasis models, identifying a novel molecular mechanism for H₂'s anti-psoriatic effects[^c41]. A 2025 study introduced a transdermal microneedle delivery system containing magnesium hydride for sustained H₂ release, which significantly outperformed standard topical therapy in an animal model of psoriasis[^c71]. Advanced delivery methods for dermatological hydrogen applications include electrospinning for hydrogen-loaded nanofibers and nano-bubble technology for enhanced skin penetration[^c86]. A 2025 study demonstrated that an oral silicon-based hydrogen-generating agent significantly reduced pressure ulcer area in a mouse model, with superior outcomes compared to hydrogen-rich water[^c84]. A 2026 study in lung cancer models under chronic intermittent hypoxia showed that H₂ suppresses tumor growth by modulating macrophage polarization toward the M1 phenotype and suppressing the CCL2-CCR2 axis[^c45]. In respiratory medicine, a 2026 study demonstrated that a silicon-based hydrogen-generating agent (elemental silicon powder mixed in feed) reduced BALF eosinophils by approximately 50% in a mouse model of allergic bronchial asthma, outperforming direct H₂ gas inhalation[^c74], and the first randomized controlled trial of inhaled hydrogen combined with tetrandrine in stage II silicosis (116 patients, 108 analyzed) demonstrated a significant improvement in lung diffusing capacity and reduced serum IL-6 compared with tetrandrine alone[^c90]. The first human pharmacokinetic study for inhaled H₂ established a minimum effective blood concentration range of 0.42 to 1.05 µg/L[^c43], and the first ratiometric fluorescent bioprobe provided direct visual confirmation that H₂ crosses the blood-brain barrier within 5 minutes of inhalation[^c42]. A randomized controlled trial of hydrogen-oxygen inhalation in 66 participants with sleep disorders demonstrated significant improvements in total sleep time, sleep efficiency, and mood[^c40]. In critical care, a 2026 case report documented that adjuvant hydrogen inhalation reversed sepsis-induced immunoparalysis in a 49-year-old patient with refractory septic shock, with deep immunophenotyping revealing biphasic resolution of T-cell exhaustion and V-shaped recovery of plasma B-cells[^c75]. The HYDRAPPET trial found that daily hydrogen-rich water consumption for eight weeks increased GLP-1 levels, reduced food cravings, improved sleep quality, and lowered cholesterol in obese adults[^c39]. A 2025 perspective article further proposed a mechanistic framework for H₂ in obesity management involving modulation of PGC-1α, irisin, and GLP-1 signaling pathways[^c53]. A 2025 comprehensive review of molecular hydrogen in liver diseases detailed H₂'s multi-target mechanisms regulating redox signaling, inflammatory cascades, glucolipid metabolism, and gut microbiota remodeling[^c44]. In auditory research, a 2026 study in Ecotoxicology and Environmental Safety demonstrated that hydrogen nanobubble water, a stabilized oral H₂ formulation with enhanced retention, protects against noise-induced hearing loss in mice through gut microbiota remodeling, NF-κB inhibition, and preservation of the blood-labyrinth barrier, establishing a gut-inner ear axis mechanism[^c66].
In liver disease, a 2026 study from Ohsawa's group demonstrated that hydrogen-water protects against acetaminophen-induced hepatotoxicity in diabetic mice and synergizes with N-acetylcysteine, with H₂ being more effective than NAC at reducing mitochondrial oxidative stress[^c52]. In autoimmune disease, a 2026 case report documented marked clinical stabilization in a 72-year-old patient with refractory primary Sjögren's syndrome-associated interstitial lung disease after oral molecular hydrogen capsule therapy, including improved pulmonary function, decreased anti-Ro antibodies, and normalization of immunophenotypic markers[^c46]. A randomized double-blind controlled trial published in BMC Women's Health found that daily hydrogen-rich water consumption significantly reduced premenstrual syndrome symptoms, including fatigue, mood swings, pain, and sleep disruption, over three menstrual cycles[^c47]. A randomized controlled pilot trial during COVID-19 lockdowns found that hydrogen-rich water consumption in adults over 70 years was associated with a 4% increase in telomere length over six months, compared to an 11% decline in controls, along with reduced C-reactive protein and improved sleep and mobility[^c48]. In oral medicine, a comprehensive review described H₂ applications in periodontitis, peri-implantitis, oral cancer, radiotherapy-related damage, and maxillofacial wound healing. A randomized trial completed in May 2026 evaluated hydrogen-rich water in 60 overweight and obese adolescents during a weight loss retreat, with results pending publication.
A 2026 study of overnight breath hydrogen dynamics in 166 healthy adults aged 20–85 years found that older adults had significantly lower morning breath hydrogen levels and larger overnight declines compared to younger adults, identifying exhaled hydrogen as a potential noninvasive biomarker for aging-related physiological changes[^c54]. Bone regeneration research advanced with a calcium silicide nanomaterial (CaSi₂) achieving a hydrogen yield of 911 mL/g and enabling sustained in situ H₂ release within scaffolds, producing a local H₂ concentration 46,000-fold higher than hydrogen-rich saline injection and enabling effective bone defect repair in aged mice[^c55]. For oral sustained hydrogen delivery, a 2022 patent described pH-dependent silicon hydride and magnesium hydride compositions enabling targeted intestinal release without enteric coatings[^c83]. Renal research advanced with a silicon-based enteric hydrogen-generating agent demonstrating approximately 400 mL H₂/g yield with renoprotective effects in a 5/6 nephrectomy rat model[^c85].
A 2026 evidence-based review of 45 studies evaluated molecular hydrogen therapy across musculoskeletal conditions, reporting symptomatic benefits but rating the GRADE evidence as low or very low across all trials[^c23]. A 2026 mouse study found that hydrogen-rich water ameliorated chronic hypoxia-induced bone degeneration and multi-organ damage through modulation of the gut microbiota, establishing a gut-bone axis mechanism of bone protection[^c91]. For a dedicated overview of osteoarthritis, rheumatoid arthritis, chronic hypoxia bone loss, and atypical femoral fracture healing, see [[clinical-evidence/musculoskeletal-and-bone-health|Musculoskeletal and Bone Health]]. In critical care, inhaled hydrogen improved survival and preserved cognitive function in sepsis models through Nrf2/HO-1 signaling and mitochondrial quality control[^c24]. A 2026 study identified SIRT1-mediated PINK1/Parkin-dependent mitophagy as a core neuroprotective mechanism of H₂ in sepsis-associated encephalopathy, with 2% H₂ inhalation increasing survival and preserving cognitive function in septic mice[^c51]. A companion 2026 study identified ATG9B as a novel H₂-responsive gene that enhances PINK1-Parkin-mediated mitophagy flux, increasing survival from 40% to 75% in septic mice[^c56]. Cardiovascular studies expanded with a Keio University trial reporting that hydrogen-rich water enhanced heart rate variability at rest in healthy adults[^c25], and a prospective observational study associated routine HRW consumption with improved lower extremity function in older adults[^c26]. In dermatology, a double-blind randomized trial found that hydrogen-rich water reduced pain and itching in keloid patients[^c27], and a mouse study showed that continuous H₂ administration delayed UVB-induced skin carcinogenesis. In oncology, a systematic review of 27 studies reported significantly improved progression-free survival in advanced NSCLC patients receiving adjunctive H₂ inhalation[^c17].
Administration routes include inhalation of hydrogen gas, drinking hydrogen-rich water, hydrogen baths, and oral solid supplements, each with distinct pharmacokinetic characteristics[^c7]. A 2025 review identified two critical unresolved issues for clinical translation: the unclear mechanism underlying H₂'s immunomodulatory effects and the lack of precision detection methods to clarify the dose-efficacy relationship in vivo[^c60]. Conventional delivery routes face critical limitations in stability, bioavailability, and targeted delivery, spurring development of advanced delivery systems including H₂-containing carriers, in situ H₂-generating materials, and externally stimulated platforms[^c31]. H₂ is a physiologically normal molecule produced by intestinal bacteria and has demonstrated no toxic side effects across exposures far exceeding therapeutic levels[^c8], though a 2026 safety study found that pure hydrogen inhalation causes a mild decrease in blood oxygen saturation from dilution of inspired oxygen[^c16]. A 2024 in vivo genotoxicity study conducted according to ICH S2(R1) guidelines confirmed that 72-hour inhalation of 3.1% H₂ does not induce DNA damage in rats[^c63]. In Japan, electrolyzed hydrogen water generators are certified as Class II medical devices for gastrointestinal symptom improvement, and hydrogen inhalation for post-cardiac arrest syndrome has been designated as an advanced medical therapy[^c9][^c10]. However, multiple severe explosion accidents have been documented from high-concentration hydrogen inhalers (67–100 vol%) that far exceed the verified safe threshold of 10 vol%[^c19].
Despite encouraging findings, the field faces significant challenges. Many studies rely on small sample sizes and exhibit methodological variability; the GRADE evidence for hydrogen in musculoskeletal conditions was rated as "low" or "very low" across all included studies[^c15]. Commercial promotion of hydrogen products has often outpaced the scientific evidence, and no national mandatory standards exist for hydrogen water concentration or quality in most countries[^c12].