{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:37:36Z","timestamp":1792816656165,"version":"4.5.0"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82405124"],"award-info":[{"award-number":["82405124"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Phloretin (PHL) is an effective monomer component of Phellodendri Chinensis Cortex, Spica Prunellae, and fleshy fruits and exerts therapeutic effects on rheumatoid arthritis (RA). However, the underlying mechanism is yet to be elucidated. Following PHL treatment, therapeutic benefits were evaluated in a collagen\u2010induced arthritis (CIA) rat model using arthritic markers and joint pathology. Network pharmacology, transcriptomics, Western blotting, IHC, molecular docking, Biacore, and cellular thermal shift assay were employed. PHL administration considerably reduced joint swelling, synovial hyperplasia, and bone erosion. Integrated network pharmacology and transcriptomic analyses identified the hypoxia\u2010inducible factor\u20101 alpha (HIF\u20101\u03b1) axis as a critical target. In\u00a0vitro experiments indicated that PHL effectively inhibited TNF\u2010\u03b1\u2010induced fibroblast\u2010like synoviocyte (FLS) proliferation, migration, invasion, and glycolytic reprogramming, promoted apoptosis, and suppressed excessive autophagy. Furthermore, in a coculture system, PHL substantially attenuated FLS\u2010induced tube formation in human umbilical vein endothelial cells. Furthermore, PHL demonstrated high affinity for HIF\u20101\u03b1 and accelerated the degradation of HIF\u20101\u03b1 protein. Importantly, HIF\u20101\u03b1 overexpression reversed PHL's inhibitory effect. RA severity was alleviated in\n                    <jats:italic>Hif1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice, validating HIF\u20101\u03b1's pathogenic role in disease progression. PHL exerts anti\u2010RA effects by targeting HIF\u20101\u03b1 to modulate glycolysis and the autophagy\u2013apoptosis balance in FLS, thereby inhibiting synovial angiogenesis. These findings provide a strong foundation for developing and applying PHL as a potential therapeutic agent for RA.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70462","type":"journal-article","created":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:03:03Z","timestamp":1792814583000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phloretin Ameliorates Rheumatoid Arthritis by Suppressing\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1\u2010Dependent Angiogenesis and Modulating of the Autophagy\u2013Apoptosis Balance"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4161-444X","authenticated-orcid":false,"given":"Liang","family":"Han","sequence":"first","affiliation":[{"name":"Department of Dermatology Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Department of Rehabilitation Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5268-262X","authenticated-orcid":false,"given":"Weiji","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ba","sequence":"additional","affiliation":[{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hubei University of Chinese Medicine  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Qin","sequence":"additional","affiliation":[{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8530-270X","authenticated-orcid":false,"given":"Shenghao","family":"Tu","sequence":"additional","affiliation":[{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-3727","authenticated-orcid":false,"given":"Pan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Dermatology Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Institute of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.molimm.2021.11.002","article-title":"Matrine Inhibits Synovial Angiogenesis in Collagen\u2010Induced Arthritis Rats by Regulating HIF\u2010VEGF\u2010Ang and Inhibiting the PI3K\/Akt Signaling Pathway","volume":"141","author":"Ao L.","year":"2022","journal-title":"Molecular Immunology"},{"issue":"1","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1016\/S2666-7568(23)00220-9","article-title":"Associations Between Biological Ageing and the Risk of, Genetic Susceptibility to, and Life Expectancy Associated With Rheumatoid Arthritis: A Secondary Analysis of Two Observational Studies","volume":"5","author":"Chen L.","year":"2024","journal-title":"Lancet Healthy 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G.","year":"2019","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s12016-025-09113-7","article-title":"CAR T Cell Therapy for Rheumatoid Arthritis","volume":"68","author":"Freeley M.","year":"2025","journal-title":"Clinical Reviews in Allergy and Immunology"},{"issue":"12","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1016\/j.ard.2025.05.019","article-title":"Influence of Canstatin on Fibroblast\u2010Driven Hypervascularisation in Rheumatoid Arthritis","volume":"84","author":"Heck C.","year":"2025","journal-title":"Annals of the Rheumatic Diseases"},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2022.109271","article-title":"Targeted Inhibition of the GRK2\/HIF\u20101\u03b1 Pathway Is an Effective Strategy to Alleviate Synovial Hypoxia and Inflammation","volume":"113","author":"Hong Z.","year":"2022","journal-title":"International Immunopharmacology"},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.00134","article-title":"Phloretin Attenuates Allergic Airway Inflammation and Oxidative Stress in Asthmatic Mice","volume":"8","author":"Huang W. C.","year":"2017","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13075-025-03647-z","article-title":"The Glycolysis\u2010HIF\u20101\u03b1 Axis Induces IL\u20101\u03b2 of Macrophages in Rheumatoid Arthritis","volume":"27","author":"Jia Y.","year":"2025","journal-title":"Arthritis Research and Therapy"},{"issue":"7","key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41584-022-00793-5","article-title":"Mechanisms of Joint Destruction in Rheumatoid Arthritis \u2010 Immune Cell\u2010Fibroblast\u2010Bone Interactions","volume":"18","author":"Komatsu N.","year":"2022","journal-title":"Nature Reviews Rheumatology"},{"issue":"20","key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"9350","DOI":"10.1039\/D3FO03523A","article-title":"Phloretin Alleviates Palmitic Acid\u2010Induced Oxidative Stress in HUVEC Cells by Suppressing the Expression of LncBAG6\u2010AS","volume":"14","author":"Li J.","year":"2023","journal-title":"Food and Function"},{"key":"e_1_2_12_13_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2018.07.009","article-title":"Succinate Induces Synovial Angiogenesis in Rheumatoid Arthritis Through Metabolic Remodeling and HIF\u20101\u03b1\/VEGF Axis","volume":"126","author":"Li Y.","year":"2018","journal-title":"Free Radical Biology and Medicine"},{"issue":"4","key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cmet.2020.08.002","article-title":"The Role of HIF in Immunity and Inflammation","volume":"32","author":"McGettrick A. F.","year":"2020","journal-title":"Cell Metabolism"},{"issue":"9","key":"e_1_2_12_15_1","first-page":"1533","article-title":"Pathogenesis of Rheumatoid Arthritis: One Year in Review 2025","volume":"43","author":"Noto G.","year":"2025","journal-title":"Clinical and Experimental Rheumatology"},{"issue":"1","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13075-024-03343-4","article-title":"Targeting Pathogenic Fibroblast\u2010Like Synoviocyte Subsets in Rheumatoid Arthritis","volume":"26","author":"Qian H.","year":"2024","journal-title":"Arthritis Research and Therapy"},{"issue":"1","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s10020-025-01181-x","article-title":"Acidosis Regulates Immune Progression in Rheumatoid Arthritis by Promoting the Expression of Cytokines and Co\u2010Stimulatory Molecules in Synovial Fibroblasts","volume":"31","author":"Qian X.","year":"2025","journal-title":"Molecular Medicine (Cambridge, Mass)"},{"issue":"3","key":"e_1_2_12_18_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2024.118921","article-title":"Wutou Decoction Attenuates Rheumatoid Arthritis in Rats Through SIRT1\u2010Mediated Deacetylation of the HMGB1\/NF\u2010\u03baB Pathway","volume":"337","author":"Shen P.","year":"2025","journal-title":"Journal of Ethnopharmacology"},{"issue":"2","key":"e_1_2_12_19_1","doi-asserted-by":"crossref","first-page":"ii3","DOI":"10.1093\/rheumatology\/keae701","article-title":"Poor Prognostic Factors and Unmet Needs in Rheumatoid Arthritis","volume":"64","author":"Smolen J. 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E.","year":"1977","journal-title":"Journal of Experimental Medicine"},{"key":"e_1_2_12_22_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2019.104489","article-title":"Phloretin Ameliorates Dextran Sulfate Sodium\u2010Induced Ulcerative Colitis in Mice by Regulating the Gut Microbiota","volume":"150","author":"Wu M.","year":"2019","journal-title":"Pharmacological Research"},{"key":"e_1_2_12_23_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2022.109556","article-title":"Hexokinase Inhibitor 2\u2010Deoxyglucose Coordinates Citrullination of Vimentin and Apoptosis of Fibroblast\u2010Like Synoviocytes by Inhibiting HK2 \/mTORC1\u2010Induced Autophagy","volume":"114","author":"Xian H.","year":"2023","journal-title":"International Immunopharmacology"},{"issue":"1","key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1021\/acs.jafc.8b05025","article-title":"Activation of Nrf2 by Phloretin Attenuates Palmitic Acid\u2010Induced Endothelial Cell Oxidative Stress via AMPK\u2010Dependent Signaling","volume":"67","author":"Yang Q.","year":"2019","journal-title":"Journal of Agricultural and Food Chemistry"},{"key":"e_1_2_12_25_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2025.156552","article-title":"Clematichinenoside AR Alleviates Rheumatoid Arthritis by Inhibiting Synovial Angiogenesis Through the HIF\u20101\u03b1\/VEGFA\/ANG2 Axis","volume":"139","author":"Yuan M.","year":"2025","journal-title":"Phytomedicine: International Journal of Phytotherapy and Phytopharmacology"},{"issue":"7987","key":"e_1_2_12_26_1","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s41586-023-06708-y","article-title":"Deconstruction of Rheumatoid Arthritis Synovium Defines Inflammatory Subtypes","volume":"623","author":"Zhang F.","year":"2023","journal-title":"Nature"},{"key":"e_1_2_12_27_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2025.107649","article-title":"The Role of HIF\u20101\u03b1 in Hypoxic Metabolic Reprogramming in Osteoarthritis","volume":"213","author":"Zhang J.","year":"2025","journal-title":"Pharmacological Research"},{"key":"e_1_2_12_28_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2025.119615","article-title":"Ermiao San Attenuating Rheumatoid Arthritis via PI3K\/AKT\/mTOR Signaling Activate HIF\u20101\u03b1 Induced Glycolysis","volume":"345","author":"Zhang Y.","year":"2025","journal-title":"Journal of Ethnopharmacology"},{"key":"e_1_2_12_29_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1633406","article-title":"The Role of Hypoxic Microenvironment in Rheumatoid Arthritis","volume":"16","author":"Zheng Q. H.","year":"2025","journal-title":"Frontiers in Immunology"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70462","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70462","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70462","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:03:06Z","timestamp":1792814586000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,23]]},"references-count":28,"alternative-id":["10.1002\/ptr.70462"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70462","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,23]]},"assertion":[{"value":"2026-01-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ptr.70462"}}