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No approved medication was currently available for NAFLD treatment. Molecular hydrogen (H<jats:sub>2<\/jats:sub>), an anti\u2010oxidative, anti\u2010inflammatory biomedical agent is proved to exhibit therapeutic and preventive effect in various diseases. The purpose of this study was to investigate the effect of hydrogen\/oxygen inhalation on NAFLD subjects and explore the mechanism from the perspective of hepatocyte autophagy. We conducted a randomized, placebo\u2010controlled clinical trial of 13\u2010week hydrogen\/oxygen inhalation (China Clinical Trial Registry [#ChiCTR\u2010IIR\u201016009114]) including 43 subjects. We found that inhalation of hydrogen\/oxygen improved serum lipid and liver enzymes. Significantly improved liver fat content detected by ultrasound and CT scans after hydrogen\/oxygen inhalation was observed in moderate\u2013severe cases. We also performed an animal experiment based on methionine and choline\u2010deficient (MCD) diet\u2010induced mice model to investigate effect of hydrogen on mouse NASH. Hydrogen\/oxygen inhalation improved systemic inflammation and liver histology. Promoted autophagy was observed in mice inhaled hydrogen\/oxygen and treatment with chloroquine blocked the beneficial effect of hydrogen. Moreover, molecular hydrogen inhibited lipid accumulation in AML\u201012 cells. Autophagy induced by palmitic acid (PA) incubation was further promoted by 20% hydrogen incubation. Addition of 3\u2010methyladenine (3\u2010MA) partially blocked the inhibitory effect of hydrogen on intracellular lipid accumulation. Collectively, hydrogen\/oxygen inhalation alleviated NAFLD in moderate\u2013severe patients. This protective effect of hydrogen was possibly by activating hepatic autophagy.<\/jats:p>","DOI":"10.1111\/jcmm.17456","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T08:33:25Z","timestamp":1655973205000},"page":"4113-4123","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["A randomized, placebo\u2010controlled clinical trial of hydrogen\/oxygen inhalation for non\u2010alcoholic fatty liver disease"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4330-5149","authenticated-orcid":false,"given":"Geru","family":"Tao","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital of Shandong First Medical University  Tai'an China"},{"name":"Taishan Institute for Hydrogen Biomedical Research Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Tai'an China"},{"name":"College of Basic Medical Sciences Shandong 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