{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:56:15Z","timestamp":1780340175719,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["U21A20407"],"award-info":[{"award-number":["U21A20407"]}]},{"name":"National Natural Science Foundation of China","award":["81973467"],"award-info":[{"award-number":["81973467"]}]},{"name":"National Natural Science Foundation of China","award":["82104364"],"award-info":[{"award-number":["82104364"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Microglia-mediated neuroinflammation is a key driver of Alzheimer\u2019s disease (AD). In AD, microglia are activated and trigger an increased secretion of pro-inflammatory factors. Rhein, an anthraquinone compound extracted from rhubarb, has been shown to reduce the secretion of pro-inflammatory cytokines including TNF-\u03b1 and IL-1\u03b2 in activated microglia. However, the mechanism of rhein on microglia-mediated neuroinflammation and neuronal damage in AD remains unclear. In this study, we found that rhein improved behavioral abnormalities in AD rats and reduced the levels of inflammatory factors such as IL-1\u03b2, iNOS, and NO in the brain of AD rats. In the LPS-induced microglial model, rhein significantly reduced the levels of inflammatory factors to improve neuroinflammation. Untargeted metabolomics showed that the reprogramming of glutamine metabolism occurred in M1 microglia. Targeted metabolomics and 13C, 15N isotope tracing experiments demonstrated that rhein regulated the metabolite levels in the glutamine\u2013aspartate\u2013arginine metabolic pathway. Meanwhile, the upregulated expression of proteins such as GLS1 and GOT1 within this pathway was reversed by rhein. Furthermore, we found that the glutamine\u2013aspartate\u2013arginine metabolic pathway regulates the production of nitric oxide (NO, a neuroinflammatory mediator). Rhein alleviates neuronal damage by inhibiting the glutamine\u2013aspartate\u2013arginine\u2013NO metabolic pathway. In conclusion, our study shows that rhein may inhibits NO production by regulating the glutamine\u2013aspartate\u2013arginine metabolic pathway in activated microglia, thereby inhibiting the neuroinflammation and neuronal damage in AD.<\/jats:p>","DOI":"10.3390\/ijms26136404","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T06:01:33Z","timestamp":1751522493000},"page":"6404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Rhein Inhibits Microglia-Mediated Neuroinflammation and Neuronal Damage of Alzheimer\u2019s Disease via Regulating the Glutamine\u2013Aspartate\u2013Arginine\u2013NO Metabolic Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Bingqing","family":"Chi","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjun","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2024). 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