{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:48:40Z","timestamp":1788835720447,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National TCM Characteristic Technology Inheritance Talent Training Program","award":["[2023] No. 96"],"award-info":[{"award-number":["[2023] No. 96"]}]},{"name":"Jiangxi Provincial TCM Young and Middle-aged Backbone Talents","award":["[2022] No. 7"],"award-info":[{"award-number":["[2022] No. 7"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81960716"],"award-info":[{"award-number":["81960716"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Jiangxi Provincial Natural Science Foundation","doi-asserted-by":"crossref","award":["20232BAB216109"],"award-info":[{"award-number":["20232BAB216109"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Purpose: The purpose of this study is to investigate the bioactive constituents of Atractylodes Rhizome (AR) and to explore its mechanism of action in the treatment of rheumatoid arthritis (RA). Methods: The research mainly adopts the methods of tissue metabolomics and network pharmacology. Firstly, we employed a metabolomics strategy to obtain the metabolite profile and utilized PCA\/OPLS-DA analyses to identify the differential metabolites involved in the treatment of RA by AR. Subsequently, we determined the key target metabolic pathways of AR in RA treatment. Next, a network pharmacology approach was employed to identify active compounds, potential targets, and signaling pathways for AR in RA treatment, with a PPI network constructed. These predictions were then validated through molecular docking simulations, followed by in vivo verification using a CFA-induced RA rat model. The anti-RA efficacy was evaluated through synovial histopathology and cytokine assays, with the key mechanistic insights being confirmed at the molecular level by RT-qPCR and WB. Results: The results of the metabolomics study showed that AR regulated 28 differential metabolites linked to glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism. Network pharmacology identified Wogonin, Atractyloyne, and Atractylenolide II as key active compounds, acting through pathways such as Pathways in cancer and PI3K-Akt signaling, combined with the metabolites to jointly analyze the metabolic pathways, and were verified by correlation analysis. Molecular docking confirmed the main active ingredients\u2019 strong binding to core targets. In AIA rats, AR treatment reduced synovial inflammation and lowered serum levels of IL-6 and MMP-9. At the molecular level, AR up-regulated Bcl-2, down-regulated Bax, and inhibited the SRC\/JAK2-STAT3 pathway by decreasing EGFR, SRC, JAK2, and p-STAT3 expression. Conclusion: These findings may illuminate the mechanism by which Atractylodes Rhizome exerts its effects via the JAK2\/SRC-STAT3 axis, thereby revealing its potential mechanism of action against rheumatoid arthritis.<\/jats:p>","DOI":"10.3390\/ph19020262","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T10:03:29Z","timestamp":1770113009000},"page":"262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrating Metabolomics and Network Pharmacology: Investigating the Therapeutic Mechanism of Atractylodes Rhizome Against Rheumatoid Arthritis"],"prefix":"10.3390","volume":"19","author":[{"given":"Rou","family":"Wen","sequence":"first","affiliation":[{"name":"School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailian","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2500-9960","authenticated-orcid":false,"given":"Chao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41590-020-00816-x","article-title":"The immunology of rheumatoid arthritis","volume":"22","author":"Weyand","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1159\/000493390","article-title":"Rheumatoid Arthritis: A Brief Overview of the Treatment","volume":"27","author":"Bullock","year":"2018","journal-title":"Med. Princ. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.immuni.2022.11.009","article-title":"The pathogenesis of rheumatoid arthritis","volume":"55","author":"Alivernini","year":"2022","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0889-857X(05)70201-5","article-title":"The epidemiology of rheumatoid arthritis","volume":"27","author":"Gabriel","year":"2001","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1001\/jama.2022.0786","article-title":"What is rheumatoid arthritis?","volume":"327","author":"Smith","year":"2022","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nrd1109","article-title":"Therapeutic strategies for rheumatoid arthritis","volume":"2","author":"Smolen","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e070856","DOI":"10.1136\/bmj-2022-070856","article-title":"Therapeutic advances in rheumatoid arthritis","volume":"384","author":"Brown","year":"2024","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1586\/1744666X.2014.917963","article-title":"Traditional Chinese medicine: Potential for clinical treatment of rheumatoid arthritis","volume":"10","author":"Moudgil","year":"2014","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.eng.2019.01.018","article-title":"Traditional Chinese Medicine as a Treatment for Rheumatoid Arthritis: From Empirical Practice to Evidence-Based Therapy","volume":"5","author":"Pan","year":"2019","journal-title":"Engineering"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1016\/j.eujim.2012.02.004","article-title":"Incorporation of traditional Chinese medicine pattern diagnosis in the management of rheumatoid arthritis","volume":"4","author":"Zhang","year":"2012","journal-title":"Eur. J. Integr. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114026","DOI":"10.1016\/j.jep.2021.114026","article-title":"Effects of rhizome of Atractylodes koreana (Nakai) Kitam on intestinal flora and metabolites in rats with rheumatoid arthritis","volume":"281","author":"Pang","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_12","unstructured":"Commission, N.P. (2025). Pharmacopoeia of the People\u2019s Republic of China, China Medical Science and Technology Press."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109965","DOI":"10.1016\/j.abb.2024.109965","article-title":"Wogonin inhibits the migration and invasion of fibroblast-like synoviocytes by targeting PI3K\/AKT\/NF-\u03baB pathway in rheumatoid arthritis","volume":"755","author":"Yang","year":"2024","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106771","DOI":"10.1016\/j.fitote.2025.106771","article-title":"Er Miao San and its main components phellodendrine and atractylenolide-I exert anti-rheumatoid arthritis effects by inhibiting PAD4 and thereby reducing the formation of NETs","volume":"185","author":"Tang","year":"2025","journal-title":"Fitoterapia"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sharma, B., and Yadav, D.K. (2022). Metabolomics and network pharmacology in the exploration of the multi-targeted therapeutic approach of traditional medicinal plants. Plants, 11.","DOI":"10.3390\/plants11233243"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/ptr.70135","article-title":"Plantaginis Semen, a Novel Natural S1PR1 Agonist, Inhibits Oxidative Stress and Inflammation to Treat Lipopolysaccharide-Induced Acute Lung Injury","volume":"40","author":"Xu","year":"2026","journal-title":"Phytother. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"175044","DOI":"10.1016\/j.ejphar.2022.175044","article-title":"Research on the effect and underlying molecular mechanism of Cangzhu in the treatment of gouty arthritis","volume":"927","author":"Li","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_18","first-page":"100768","article-title":"Risk of cancer for patients with rheumatoid arthritis versus general population: A national claims database cohort study","volume":"35","author":"Beydon","year":"2023","journal-title":"Lancet Reg. Health"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.biopha.2018.03.123","article-title":"Cancer chemotherapeutics in rheumatoid arthritis: A convoluted connection","volume":"102","author":"Jayashree","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bobkova, T., Bobkov, A., and Li, Y. (2025). Pharmacological Inhibition of the PI3K\/AKT\/mTOR Pathway in Rheumatoid Arthritis Synoviocytes: A Systematic Review and Meta-Analysis (Preclinical). Pharmaceuticals, 18.","DOI":"10.3390\/ph18081152"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"108875","DOI":"10.1016\/j.biopha.2019.108875","article-title":"Metformin inhibits the proliferation of rheumatoid arthritis fibroblast-like synoviocytes through IGF-IR\/PI3K\/AKT\/m-TOR pathway","volume":"115","author":"Chen","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"113039","DOI":"10.1016\/j.jep.2020.113039","article-title":"Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K\/AKT and MAPKs signaling pathways","volume":"260","author":"Liu","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bbrc.2022.02.003","article-title":"Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulating the IL-6\/JAK signaling pathway","volume":"600","author":"Su","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, C., Wen, R., Liu, D., Yan, L., Gong, Q., and Yu, H. (2022). Assessment of the potential of Sarcandra glabra (thunb.) nakai. In treating ethanol-induced gastric ulcer in rats based on metabolomics and network analysis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.810344"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Yang, J., Qu, B., Huang, J., Wang, Y., and Yan, J. (2025). Enhanced Anti-Lung Cancer Effects of Steamed Panacis Japonici Rhizoma: Insights from Metabolomics, Network Pharmacology and Molecular Dynamics Simulation. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262411999"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liu, Y., Lu, W., Xiang, Z., Shen, Y., Ni, B., Zou, H., and Shao, X. (2025). Integrated bioinformatics and machine learning reveal pan-apoptosis and immune infiltration signatures in diabetic nephropathy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1659065"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Obeidat, A.M., Kim, S.Y., Burt, K.G., Hu, B., Li, J., Ishihara, S., Xiao, R., Miller, R.E., Little, C., and Malfait, A.-M. (2023). Recommendations For a Standardized Approach to Histopathologic Evaluation of Synovial Membrane in Murine Models of Experimental Osteoarthritis. bioRxiv.","DOI":"10.1101\/2023.10.14.562259"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e11772","DOI":"10.1002\/acr2.11772","article-title":"Patient-Reported Fatigue Associated with Joint Histopathology in Rheumatoid Arthritis","volume":"7","author":"Smith","year":"2025","journal-title":"ACR Open Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/biof.1585","article-title":"Wogonin ameliorate complete Freund\u2019s adjuvant induced rheumatoid arthritis via targeting NF-\u03baB\/MAPK signaling pathway","volume":"46","author":"Huang","year":"2020","journal-title":"Biofactors"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jep.2009.06.003","article-title":"Antipyretic and anti-inflammatory properties of the ethanolic extract, dichloromethane fraction and costunolide from Magnolia ovata (Magnoliaceae)","volume":"124","author":"Kassuya","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1186\/s13075-023-03208-2","article-title":"Comprehensive multi-omics analysis reveals the core role of glycerophospholipid metabolism in rheumatoid arthritis development","volume":"25","author":"Jian","year":"2023","journal-title":"Arthritis Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1007\/s10753-020-01246-5","article-title":"Cinnamaldehyde Attenuates the Progression of Rheumatoid Arthritis through Down-Regulation of PI3K\/AKT Signaling Pathway","volume":"43","author":"Li","year":"2020","journal-title":"Inflammation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116507","DOI":"10.1016\/j.jpba.2024.116507","article-title":"Integrated network pharmacology, metabolomics and molecular docking analysis to reveal the mechanisms of quercetin in the treatment of hyperlipidemia","volume":"252","author":"Chen","year":"2025","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lu, L., Huang, C., Zhou, Y., Jiang, H., Chen, C., Du, J., Zhou, T., Wen, F., Pei, J., and Wu, Q. (2024). Tinosporae Radix attenuates acute pharyngitis by regulating glycerophospholipid metabolism and inflammatory responses through PI3K-Akt signaling pathway. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1491321"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"156336","DOI":"10.1016\/j.phymed.2024.156336","article-title":"Chuanxiong Qingnao Granules (CQG) alleviates nitroglycerin-induced migraine-like pain in rats by glycerophospholipid metabolism and PI3K\/Akt signaling pathway","volume":"136","author":"Hou","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e509","DOI":"10.1002\/mco2.509","article-title":"Rheumatoid arthritis: Pathogenesis and therapeutic advances","volume":"5","author":"Gao","year":"2024","journal-title":"MedComm"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Wang, P., Lei, T., Guo, J., Jiang, Y., Li, Y., Zheng, J., Wang, S., Xu, H., and Jian, G. (2025). The role and impact of the IL-6 mediated JAK2-STAT1\/3 signaling pathway in the pathogenesis of gout. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1480844"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10067-012-2119-9","article-title":"Epidermal growth factor receptor (EGFR) as a therapeutic target in rheumatoid arthritis","volume":"32","author":"Yuan","year":"2013","journal-title":"Clin. Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41416-022-01794-7","article-title":"SBSN drives bladder cancer metastasis via EGFR\/SRC\/STAT3 signalling","volume":"127","author":"Zhou","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Liu, J., Zhang, M., Wei, S., Li, R., Gao, Y., Peng, W., and Wu, C. (2019). Apoptosis induction of fibroblast-like synoviocytes is an important molecular-mechanism for herbal medicine along with its active components in treating rheumatoid arthritis. Biomolecules, 9.","DOI":"10.3390\/biom9120795"},{"key":"ref_41","first-page":"9013169","article-title":"Resveratrol inhibits MMP3 and MMP9 expression and secretion by suppressing TLR4\/NF-\u03baB\/STAT3 activation in Ox-LDL-treated HUVECs","volume":"2019","author":"Zhang","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"F25","DOI":"10.1152\/ajprenal.00311.2016","article-title":"Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production","volume":"312","author":"Matsui","year":"2017","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/sj.leu.2401415","article-title":"Inhibition of constitutively activated Stat3 correlates with altered Bcl-2\/Bax expression and induction of apoptosis in mycosis fungoides tumor cells","volume":"13","author":"Nielsen","year":"1999","journal-title":"Leukemia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1471-4892(03)00037-7","article-title":"The role of apoptosis in rheumatoid arthritis","volume":"3","author":"Liu","year":"2003","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Youssef, M.E., Abdel-Reheim, M.A., Morsy, M.A., El-Daly, M., Atwa, G.M., Yahya, G., Cavalu, S., Saber, S., and Ahmed Gaafar, A.G. (2022). Ameliorative effect of dabigatran on CFA-induced rheumatoid arthritis via modulating kallikrein-kinin system in rats. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810297"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Li, C., Wen, R., Liu, D.W., Liu, Q., Yan, L.P., Wu, J.X., Li, S.Y., Gong, Q.F., and Yu, H. (2020). Diuretic Effect and Metabolomics Analysis of Crude and Salt-Processed Plantaginis Semen. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.563157"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kumar, A., and Patil, C. (2025). Network Pharmacology: Principles, Processes, and Applications, CRC Press.","DOI":"10.1201\/9781003500964"},{"key":"ref_48","first-page":"164","article-title":"Analysis of chemical compositions in Atractylodes lancea Rhizoma before and after processing with rice-washed water by UPLC-Q-TOF-MS","volume":"28","author":"Wang","year":"2022","journal-title":"Chin. J. Exp. Tradit. Med. Form"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15165","DOI":"10.2147\/JIR.S564356","article-title":"Integration of Network Pharmacology, Molecular Docking, and Experimental Validation to Identify the Effect of EGCG on Alleviating Chondrocyte Inflammatory Damage by Targeting ER Stress-STAT3 Crosstalk","volume":"18","author":"Zhao","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: Improved protein\u2013ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/2\/262\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T05:20:11Z","timestamp":1770268811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/2\/262"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,3]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ph19020262"],"URL":"https:\/\/doi.org\/10.3390\/ph19020262","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,3]]}}}