{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:18:55Z","timestamp":1784870335960,"version":"3.55.0"},"reference-count":109,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"content-version":"vor","delay-in-days":353,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002369","name":"Chongqing University","doi-asserted-by":"publisher","award":["SOMS20240NXM-013"],"award-info":[{"award-number":["SOMS20240NXM-013"]}],"id":[{"id":"10.13039\/501100002369","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Nontraumatic osteonecrosis of the femoral head (NONFH) is a devastating condition characterised by immune dysregulation and sterile inflammation, which are increasingly acknowledged as central pathogenic mechanisms. This study aims to identify the core herbal combination for NONFH and systematically explore its immunomodulatory effects and underlying pharmacological mechanisms, with a focus on immune system interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The core combination \u2018Rehmanniae radix praeparata (SDH)\u2010achyranthes root (NX)\u2010Chinese angelica root (DG)\u2019 (SND) was identified via data mining of clinical literature using the Traditional Chinese Medicine Inheritance Support System (TCMISS) V2.5 platform. Its chemical constituents were characterised by ultrahigh performance liquid chromatography\u2010quadrupole time\u2010of\u2010flight mass spectrometry (UHPLC\u2010Q\u2010TOF\u2010MS\n                      <jats:sup>E<\/jats:sup>\n                      ) technology, yielding 127 identified compounds, 47 of which were selected as bioactive components based on drug\u2010likeness screening. The potential molecular targets of SND and NONFH were predicted and intersected, with a focus on immune\u2010related targets. Subsequent comprehensive enrichment analysis was performed, emphasising immune pathway involvement, along with immune infiltration profiling. A support vector machine (SVM) model was constructed to identify key immune\u2010related targets, and interactions were validated via molecular docking and molecular dynamics (MD) simulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SND shared 46 candidate targets with NONFH. Enrichment analysis revealed these targets were significantly enriched in immune\u2010inflammatory pathways, especially those related to immune cell activation and regulation. Notably, pathways involved in neutrophil extracellular trap (NET) formation and other innate immune responses were prominent. Machine learning identified five key targets: ACP1, NDUFAF3, haematopoietic cell kinase (HCK), CXCR2 and platelet\u2010activating factor receptor (PTAFR)\u2014all of which play critical roles in the modulation, signalling and activation of immune cells, particularly neutrophils and macrophages. Subsequent immune infiltration analysis demonstrated a strong correlation between these key targets (e.g. HCK, CXCR2 and PTAFR) and neutrophil abundance in NONFH. Molecular docking (MD) and molecular dynamics simulations (MDS). MD confirmed stable binding between the active components and these targets, with the HCK\u2010chrysophanic acid complex exhibiting the strongest affinity (binding energy: \u22128.7\u2009kcal\/mol).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our integrated analysis suggests that SND alleviates NONFH primarily through multi\u2010target immunomodulation, explicitly involving suppression of NET formation and regulation of immune cell activity, especially neutrophils and osteoclasts. This study presents a novel, immunologically explicit hypothesis for the mechanism of SND against NONFH, providing a solid theoretical foundation for future experimental validation and clinical application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/mi\/2808908","type":"journal-article","created":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T12:40:42Z","timestamp":1766234442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunomodulatory Mechanisms of Rehmanniae Radix Praeparata\u2013Achyranthes Root\u2013Chinese Angelica Root Combination in Nontraumatic Osteonecrosis of the Femoral Head: A Comprehensive Network Pharmacology and Molecular Docking Study Focusing on Immunological Pathways"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-0767","authenticated-orcid":false,"given":"Xin","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-0012","authenticated-orcid":false,"given":"Liqi","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4576-8753","authenticated-orcid":false,"given":"Caiying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9443-7080","authenticated-orcid":false,"given":"Leilei","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0266-392X","authenticated-orcid":false,"given":"Pengcheng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9854-4043","authenticated-orcid":false,"given":"Chaozong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6769-3802","authenticated-orcid":false,"given":"Yusong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3816-4756","authenticated-orcid":false,"given":"Qiuping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-2985","authenticated-orcid":false,"given":"Wei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3065-4625","authenticated-orcid":false,"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"e_1_2_14_1_2","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2024.2416070"},{"key":"e_1_2_14_2_2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.19.01271"},{"key":"e_1_2_14_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2019.12.004"},{"key":"e_1_2_14_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/os.12857"},{"key":"e_1_2_14_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11999-010-1292-x"},{"key":"e_1_2_14_6_2","doi-asserted-by":"publisher","DOI":"10.3109\/14397595.2014.932038"},{"key":"e_1_2_14_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-018-04826-2"},{"key":"e_1_2_14_8_2","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620X.102B7.BJJ-2019-1611.R1"},{"key":"e_1_2_14_9_2","doi-asserted-by":"publisher","DOI":"10.5435\/JAAOS-22-07-455"},{"key":"e_1_2_14_10_2","doi-asserted-by":"publisher","DOI":"10.4103\/1735-1995.200273"},{"key":"e_1_2_14_11_2","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.168017"},{"key":"e_1_2_14_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldaa044"},{"key":"e_1_2_14_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1428125"},{"key":"e_1_2_14_14_2","doi-asserted-by":"publisher","DOI":"10.5312\/wjo.v16.i5.106377"},{"key":"e_1_2_14_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03271-6"},{"key":"e_1_2_14_16_2","doi-asserted-by":"publisher","DOI":"10.1155\/mi\/8742817"},{"key":"e_1_2_14_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2021.116012"},{"key":"e_1_2_14_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_2_14_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-10-463646"},{"key":"e_1_2_14_20_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000026811"},{"key":"e_1_2_14_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13018-023-04086-9"},{"key":"e_1_2_14_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000012196"},{"key":"e_1_2_14_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-025-01113-1"},{"key":"e_1_2_14_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.111862"},{"key":"e_1_2_14_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2020.03.014"},{"key":"e_1_2_14_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115628"},{"key":"e_1_2_14_27_2","doi-asserted-by":"publisher","DOI":"10.2174\/1573409919666230605123129"},{"key":"e_1_2_14_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-021-00338-z"},{"key":"e_1_2_14_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2011.12.027"},{"key":"e_1_2_14_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/md23030114"},{"key":"e_1_2_14_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2023.117682"},{"key":"e_1_2_14_32_2","doi-asserted-by":"publisher","DOI":"10.3390\/foods13172685"},{"key":"e_1_2_14_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/foods13213354"},{"key":"e_1_2_14_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_14_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz382"},{"key":"e_1_2_14_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0294236"},{"key":"e_1_2_14_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"e_1_2_14_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-024-02050-4"},{"key":"e_1_2_14_39_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40122-024-00700-8"},{"key":"e_1_2_14_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2022.105739"},{"key":"e_1_2_14_41_2","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1794974"},{"key":"e_1_2_14_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2019.04.003"},{"key":"e_1_2_14_43_2","doi-asserted-by":"publisher","DOI":"10.19540\/j.cnki.cjcmm.20230614.302"},{"key":"e_1_2_14_44_2","first-page":"911","article-title":"Structure Elucidation of Degradation Products of Z-Ligustilide by UPLC-QTOF-MS and NMR Spectroscopy","volume":"48","author":"Zuo A. H.","year":"2013","journal-title":"Yao xue xue bao\u2009=\u2009Acta Pharmaceutica Sinica"},{"key":"e_1_2_14_45_2","doi-asserted-by":"publisher","DOI":"10.19540\/j.cnki.cjcmm.20240426.301"},{"key":"e_1_2_14_46_2","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2021.36.e65"},{"key":"e_1_2_14_47_2","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.912133"},{"key":"e_1_2_14_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114403"},{"key":"e_1_2_14_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2020.07.008"},{"key":"e_1_2_14_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11655-016-2407-3"},{"key":"e_1_2_14_51_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11655-011-0637-y"},{"key":"e_1_2_14_52_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-014-0334-7"},{"key":"e_1_2_14_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2023.127428"},{"key":"e_1_2_14_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2019.01.026"},{"key":"e_1_2_14_55_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.40917"},{"key":"e_1_2_14_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115809"},{"key":"e_1_2_14_57_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24020253"},{"key":"e_1_2_14_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.119549"},{"key":"e_1_2_14_59_2","doi-asserted-by":"publisher","DOI":"10.3724\/SP.J.1009.2013.00577"},{"key":"e_1_2_14_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2024.119118"},{"key":"e_1_2_14_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.4959"},{"key":"e_1_2_14_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2011.07.019"},{"key":"e_1_2_14_63_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu6104362"},{"key":"e_1_2_14_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-025-00412-5"},{"key":"e_1_2_14_65_2","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/7153584"},{"key":"e_1_2_14_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2014.08.018"},{"key":"e_1_2_14_67_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.6b07808"},{"key":"e_1_2_14_68_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13239"},{"key":"e_1_2_14_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.01.013"},{"key":"e_1_2_14_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2006.12.007"},{"key":"e_1_2_14_71_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11040992"},{"key":"e_1_2_14_72_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-013-9402-5"},{"key":"e_1_2_14_73_2","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0829"},{"key":"e_1_2_14_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms16003"},{"key":"e_1_2_14_75_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82585"},{"key":"e_1_2_14_76_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a002352"},{"key":"e_1_2_14_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2013.11.010"},{"key":"e_1_2_14_78_2","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2018.1553266"},{"key":"e_1_2_14_79_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-232736"},{"key":"e_1_2_14_80_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-023-00251-2"},{"key":"e_1_2_14_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2008.03.008"},{"key":"e_1_2_14_82_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-024-00708-3"},{"key":"e_1_2_14_83_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-024-02106-z"},{"key":"e_1_2_14_84_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu14204414"},{"key":"e_1_2_14_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2009.02.007"},{"key":"e_1_2_14_86_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20504"},{"key":"e_1_2_14_87_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2009.05.007"},{"key":"e_1_2_14_88_2","first-page":"61","article-title":"[Allele Polymorphism of Alkaline Phosphatase, Acid Soluble Phosphatase, and Vitamin D-Binding Protein Genes in Postmenopausal Osteoporosis]","volume":"76","author":"Krylov M.","year":"2004","journal-title":"Terapevticheskii Arkhiv"},{"key":"e_1_2_14_89_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-311969"},{"key":"e_1_2_14_90_2","doi-asserted-by":"publisher","DOI":"10.2217\/pgs-2019-0087"},{"key":"e_1_2_14_91_2","first-page":"2227","article-title":"Low Molecular Weight Protein Tyrosine Phosphatase Slow Isoform Knockdown in MDA-MB-435 Cells Decreases RAW 264.7 Osteoclastic Differentiation","volume":"36","author":"Alho I.","year":"2016","journal-title":"Anticancer Research"},{"key":"e_1_2_14_92_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24691"},{"key":"e_1_2_14_93_2","doi-asserted-by":"publisher","DOI":"10.1159\/000185506"},{"key":"e_1_2_14_94_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00476"},{"key":"e_1_2_14_95_2","doi-asserted-by":"publisher","DOI":"10.1159\/000491742"},{"key":"e_1_2_14_96_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41649"},{"key":"e_1_2_14_97_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41536-024-00364-0"},{"key":"e_1_2_14_98_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep42681"},{"key":"e_1_2_14_99_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.315762"},{"key":"e_1_2_14_100_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.335"},{"key":"e_1_2_14_101_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102869"},{"key":"e_1_2_14_102_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2023.107675"},{"key":"e_1_2_14_103_2","doi-asserted-by":"publisher","DOI":"10.1080\/13510002.2025.2491846"},{"key":"e_1_2_14_104_2","doi-asserted-by":"publisher","DOI":"10.1530\/EOR-24-0023"},{"key":"e_1_2_14_105_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom9020068"},{"key":"e_1_2_14_106_2","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.13143"},{"key":"e_1_2_14_107_2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12871"},{"key":"e_1_2_14_108_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2011.08.010"},{"key":"e_1_2_14_109_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-67442-3"}],"container-title":["Mediators of Inflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/mi\/2808908","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/mi\/2808908","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/mi\/2808908","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:21:32Z","timestamp":1773008492000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/mi\/2808908"}},"subtitle":[],"editor":[{"given":"Wencai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":109,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1155\/mi\/2808908"],"URL":"https:\/\/doi.org\/10.1155\/mi\/2808908","archive":["Portico"],"relation":{},"ISSN":["0962-9351","1466-1861"],"issn-type":[{"value":"0962-9351","type":"print"},{"value":"1466-1861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2025-09-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2808908"}}