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Qi Jing Wan (QJW), a traditional herbal formula composed of Angelica sinensis, Astragalus membranaceus, and Rhizoma Polygonati Odorati, has demonstrated potential efficacy in treating cognitive disorders. However, its effects on cognitive dysfunction in plateau hypoxic environments remain unclear. Methods: In this study, acute and chronic plateau cognitive impairment mouse models were constructed to investigate the preventive and therapeutic effects of QJW and its significant active ingredient, diosgenin (Dio). Behavioral experiments were conducted to assess learning and memory in mice. Morphological changes in hippocampal neurons and synapses were assessed, and microglial activation and inflammatory factor levels were measured to evaluate brain damage. Potential active ingredients capable of crossing the blood\u2013brain barrier were identified through chemical composition analysis and network database screening, followed by validation in animal and brain organoid experiments. Transcriptomics analysis, immunofluorescence staining, and molecular docking techniques were employed to explore the underlying mechanisms. Results: QJW significantly enhanced learning and memory abilities in plateau model mice, reduced structural damage to hippocampal neurons, restored NeuN expression, inhibited inflammatory factor levels and microglial activation, and improved hippocampal synaptic damage. Transcriptomics analysis revealed that Dio alleviated hypoxic brain damage and protected cognitive function by regulating the expression of PDE4C. Conclusions: These findings indicate that QJW and its significant active ingredient Dio effectively mitigate hypoxic brain injury and prevent cognitive impairment in high-altitude environments.<\/jats:p>","DOI":"10.3390\/ph18050738","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T06:54:28Z","timestamp":1747724068000},"page":"738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neuroprotective Effects of Qi Jing Wan and Its Active Ingredient Diosgenin Against Cognitive Impairment in Plateau Hypoxia"],"prefix":"10.3390","volume":"18","author":[{"given":"Tiantian","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Tranditional Chinese Medicine, Qinghai Unversity Medical College, Xining 810016, China"},{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziqiao","family":"Yan","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"},{"name":"Chinese PLA Medical School, Chinese People\u2019s Liberation Army (PLA) General Hospital, Beijing 100036, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pan","family":"Shen","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyang","family":"Chang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"},{"name":"National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Tranditional Chinese Medicine, Qinghai Unversity Medical College, Xining 810016, China"},{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"},{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"},{"name":"Chinese PLA Medical School, Chinese People\u2019s Liberation Army (PLA) General Hospital, Beijing 100036, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"General Hospital of Xinjiang Military Command, PLA, Urumqi 830000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Tranditional Chinese Medicine, Qinghai Unversity Medical College, Xining 810016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0435-7261","authenticated-orcid":false,"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-2398","authenticated-orcid":false,"given":"Zhexin","family":"Ni","sequence":"additional","affiliation":[{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Tranditional Chinese Medicine, Qinghai Unversity Medical College, Xining 810016, China"},{"name":"Beijing Institute of Radiation Medicine, Beijing 100850, China"},{"name":"State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s11065-004-8159-4","article-title":"Neuropsychological functioning associated with high-altitude exposure","volume":"14","author":"Garrido","year":"2004","journal-title":"Neuropsychol. 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