{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:55:43Z","timestamp":1790618143389,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Cell Communication and Signaling"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Iron dysregulation has emerged as a contributor to osteoarthritis (OA), yet the cell\u2010communication mechanisms connecting iron\u2010related genetic signals to joint degeneration remain insufficiently defined. Here, we established an integrative computational framework combining transcriptomic screening, machine learning, Mendelian randomization, immune and metabolite mediation analysis, single\u2010cell transcriptomics, virtual gene perturbation, molecular docking, molecular dynamics simulation, and experimental validation to identify signaling regulators involved in iron metabolism\u2010associated OA. By intersecting iron metabolism\u2010related genes, OA differentially expressed genes, and eQTL\u2010supported genes, we identified 27 shared candidates. Machine learning\u2010based prioritization and genetic causal inference further highlighted\n                    <jats:italic>CSF1R<\/jats:italic>\n                    as a central regulatory gene. Single\u2010cell analysis localized CSF1R expression predominantly to macrophages, indicating a macrophage\u2010centered role in the osteoarthritic microenvironment. Mediation analysis integrating 731 immune\u2010cell traits and 1400 circulating metabolites identified CD14\n                    <jats:sup>+<\/jats:sup>\n                    CD16\n                    <jats:sup>+<\/jats:sup>\n                    monocytes as a significant cellular mediator linking\n                    <jats:italic>CSF1R<\/jats:italic>\n                    activity to OA susceptibility, suggesting that\n                    <jats:italic>CSF1R<\/jats:italic>\n                    may promote disease progression mainly through monocyte\u2013macrophage remodeling rather than isolated metabolic alteration. Genetic colocalization further supported a shared regulatory signal between\n                    <jats:italic>CSF1R<\/jats:italic>\n                    expression and OA risk. Virtual single\u2010cell perturbation revealed distinct downstream consequences of\n                    <jats:italic>CSF1R<\/jats:italic>\n                    modulation. Simulated\n                    <jats:italic>CSF1R<\/jats:italic>\n                    depletion enhanced antigen processing, major histocompatibility complex class II presentation, and phagosome\u2010related programs, whereas simulated\n                    <jats:italic>CSF1R<\/jats:italic>\n                    overexpression preferentially activated extracellular matrix organization, integrin signaling, and cartilage development\u2010associated pathways. Structural analyses identified stable interactions between\n                    <jats:italic>CSF1R<\/jats:italic>\n                    and candidate inhibitory compounds, and inflammatory stimulation of macrophages confirmed increased\n                    <jats:italic>CSF1R<\/jats:italic>\n                    protein expression. Collectively, this study identifies\n                    <jats:italic>CSF1R<\/jats:italic>\n                    as a macrophage\u2010associated immunometabolic signaling hub linking iron dysregulation to OA. These findings provide a mechanistic basis for targeting\n                    <jats:italic>CSF1R<\/jats:italic>\n                    \u2010mediated monocyte\u2013macrophage communication and offer a computational strategy for prioritizing therapeutic targets in degenerative joint disease.\n                  <\/jats:p>","DOI":"10.1002\/ccs3.70107","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:19:17Z","timestamp":1787825957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virtual single\u2010cell perturbation and genetic causal inference reveal\n                    <i>CSF1R<\/i>\n                    \u2010dependent immunometabolic communication in iron metabolism\u2010associated osteoarthritis"],"prefix":"10.1002","volume":"20","author":[{"given":"Yue","family":"Zhou","sequence":"first","affiliation":[{"name":"Affiliated Hospital of North Sichuan Medical College  Nanchong Sichuan China"},{"name":"North Sichuan Medical College  Nanchong Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8551-2885","authenticated-orcid":false,"given":"Guohang","family":"Shen","sequence":"additional","affiliation":[{"name":"North Sichuan Medical College  Nanchong Sichuan China"},{"name":"Department of Clinical Medicine Ningxia Medical University  Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijing","family":"Si","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of North Sichuan Medical College  Nanchong Sichuan China"},{"name":"North Sichuan Medical College  Nanchong Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Ningxia Medical University  Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Ningxia Medical University  Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyan","family":"Wang","sequence":"additional","affiliation":[{"name":"North Sichuan Medical College  Nanchong Sichuan China"},{"name":"School of Basic Medicine and Forensic Medicine North Sichuan Medical College  Nanchong Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8854-3598","authenticated-orcid":false,"given":"Yupei","family":"Dai","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of North Sichuan Medical College  Nanchong Sichuan China"},{"name":"Department of Clinical Medicine Ningxia Medical University  Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adu2294"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2025.123395"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010025\u201001223\u2010y"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252212082"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412817"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1604652"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010025\u201000907\u20100"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/lifemedi\/lnaf032"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.121020"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920\u2010025\u201002206\u20104"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac963"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq537"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201095740\u20101"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.16536"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2025.101547"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241814099"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.922195"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2026.117181"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2026.110902"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2025.107066"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010026\u201002995\u20102"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2026.2647487"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/19476035231223455"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1790804"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.14670\/hh\u201025\u2010106"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2026.168369"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ocarto.2020.100030"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1825725"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2026.5923"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010026\u201003147\u20102"}],"container-title":["Journal 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