{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:34:06Z","timestamp":1789439646367,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82074109"],"award-info":[{"award-number":["82074109"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374133"],"award-info":[{"award-number":["82374133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Rehmanniae Radix<\/jats:italic>\n                    (RR) has a long history in treating type 2 diabetes mellitus (T2DM). It was previously shown to alleviate T2DM through the regulation of molecular targets in the kidney. However, the role of RR on T2DM\u2010driven hepatic metabolism disorder remains unclear. This study aimed to elucidate the therapeutic effects of RR against T2DM and reveal its mechanism of action in the liver. In this study, a high\u2010fat diet and streptozotocin\u2010induced T2DM rat model were used to investigate the antidiabetic effect of\n                    <jats:italic>Rehmanniae Radix<\/jats:italic>\n                    extract (RRE). Proteomics and metabolomics of rat serum and livers were employed to predict antidiabetic targets and metabolic pathways of RRE in the treatment of T2DM. After 5\u2010week oral administration, low, medium, and high doses of RRE all exhibited significant hypoglycemic effects, notably improving insulin resistance in T2DM rats. Additionally, 78 differentially expressed proteins returning to normal levels were identified in the serum, whereas 83 and 69 differentially expressed metabolites returning to normal levels were identified in the serum and liver, respectively. KEGG enrichment analysis from the proteomics and metabolomics data revealed enrichment of both ATP\u2010binding cassette (ABC) transporters and multiple lipid metabolism\u2010related pathways, which are highly associated with the antidiabetic effect of RRE. Pearson's correlation analysis showed significant correlations between differential proteins involved in cholesterol metabolism and differential metabolites related to lipid metabolism pathways in serum and liver. Furthermore, RT\u2010qPCR results demonstrated significant downregulation of mRNA levels of ATP\u2010binding cassette transporter A1 (Abca1) and ATP\u2010binding cassette subfamily G member 5 (Abcg5), upregulation of mRNA level of Glucose transporter type 1 (Glut1) and a decrease in hepatic glycogen content in the RRE\u2010treated T2DM rats. In conclusion, RRE exhibits a potent antidiabetic effect by downregulating Abca1 and Abcg5 to inhibit hepatic cholesterol efflux, promoting low\u2010density lipoprotein cholesterol clearance, upregulating Glut1 to increase hepatic glucose uptake, and lowering blood glucose levels, thereby improving glucose and lipid metabolism disorders.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501294r","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T08:54:12Z","timestamp":1751964852000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integration of Pharmacodynamics, Proteomics, and Metabolomics to Elucidate Effect and Mechanism of\n                    <i>Rehmanniae Radix<\/i>\n                    in the Treatment of\n                    <scp>T2DM<\/scp>"],"prefix":"10.1096","volume":"39","author":[{"given":"Jingru","family":"Liang","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxia","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai 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University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiandian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarong","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Chow","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longzhou","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5524-7172","authenticated-orcid":false,"given":"Guo","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"e_1_2_13_2_1","volume-title":"IDF Diabetes Atlas","author":"International Diabetes Federation","year":"2025"},{"key":"e_1_2_13_3_1","first-page":"132","volume-title":"Rehmannia glutinosa Pharmacopoeia of the People's Republic of China","author":"Chinese Pharmacopoeia Commission","year":"2025"},{"key":"e_1_2_13_4_1","first-page":"7575","article-title":"Research Progress on Mechanism of Rehmanniae Radix in Treatment of Type 2 Diabetes Mellitus","volume":"53","author":"Tian W. 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