{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:47:22Z","timestamp":1791877642726,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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":["82304069"],"award-info":[{"award-number":["82304069"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M734003"],"award-info":[{"award-number":["2023M734003"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515010086"],"award-info":[{"award-number":["2023A1515010086"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical & Translational Med"],"published-print":{"date-parts":[[2026,10]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Thoracic radiotherapy can cause delayed cardiac fibrosis, but the immune mechanisms linking radiation injury to fibroblast activation remain unclear. We investigated whether CCR2\n +<\/jats:sup>\n monocytes contribute to radiation\u2010induced cardiac fibrosis and whether AXL regulates their fibroblast\u2010activating activity.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and materials<\/jats:title>\n \n C57BL\/6 mice received 20\u00a0Gy whole\u2010thorax irradiation, and remodelling was assessed from IR_D0 to IR_D60. Bulk RNA sequencing was integrated with single\u2010cell datasets and CIBERSORTx deconvolution, lineage tracing, and tissue staining. CCR2\n +<\/jats:sup>\n monocyte function was examined by CCR2 neutralisation, and circulating CCR2\n +<\/jats:sup>\n Ly6C\u02b0\n i<\/jats:sup>\n monocytes were quantified by flow cytometry. AXL was investigated using inducible myeloid Axl deletion and bemcentinib (R428). MAPK signalling was assessed by transcriptomic analysis and immunoblotting of sorted CCR2\n +<\/jats:sup>\n Ly6C\u02b0\n i<\/jats:sup>\n monocytes. Conditioned medium from sorted monocytes after Axl deletion, AXL inhibition with R428, or MEK1\/2 inhibition with U0126 was applied to cardiac fibroblasts.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Cardiac fibrosis was established by IR_D30, while leukocyte infiltration and apoptotic signals remained above baseline. Transcriptomic analyses and lineage tracing showed increased cardiac accumulation of CCR2\n +<\/jats:sup>\n monocytes. CCR2 neutralisation reduced circulating CCR2\n +<\/jats:sup>\n Ly6C\u02b0\n i<\/jats:sup>\n monocytes and attenuated interstitial collagen deposition and fibrotic marker expression. Axl was enriched in the CCR2\n +<\/jats:sup>\n monocyte compartment. Myeloid Axl deletion and R428 reduced cardiac fibrosis. Axl deletion suppressed MAPK\u2010related transcriptional programs, whereas genetic or pharmacological AXL targeting reduced MEK and ERK phosphorylation in sorted monocytes. Conditioned medium from IR_D30 monocytes induced COL1A1 and \u03b1\u2010SMA expression in fibroblasts, and this effect was reduced by Axl deletion, R428, or U0126 treatment of donor monocytes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n AXL signalling contributes to the fibroblast\u2010activating paracrine activity of cardiac CCR2\n +<\/jats:sup>\n monocytes after irradiation, at least in part through MEK\/ERK signalling.\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Radiation exposure induces cardiac fibrosis through immunestromal interactions.<\/jats:p>\n <\/jats:list-item>\n \n \n CCR2\n +<\/jats:sup>\n monocytes promote fibroblast activation during radiation-induced cardiac fibrosis.\n <\/jats:p>\n <\/jats:list-item>\n \n AXL regulates monocyte\u2010mediated fibroblast activation through MEK\/ERK signaling.<\/jats:p>\n <\/jats:list-item>\n \n Targeting the AXL\u2010MEK\/ERK pathway may provide a potential strategy for preventing radiation\u2010induced cardiac fibrosis.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/ctm2.70852","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:06:34Z","timestamp":1791875194000},"source":"Crossref","is-referenced-by-count":0,"title":["Radiation\u2010induced AXL upregulation in CCR2\n +<\/sup>\n monocytes promotes cardiac fibrosis"],"prefix":"10.1002","volume":"16","author":[{"given":"Ying\u2010Yi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Centre for Cancer Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Centre Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Qi","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8777-0646","authenticated-orcid":false,"given":"Zhi\u2010Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Centre for Cancer Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Centre Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Institute of Precision Medicine Centre for Translational Medicine The First Affiliated Hospital of Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4545-5829","authenticated-orcid":false,"given":"Yi\u2010Xin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Centre for Cancer Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Centre Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Xin","family":"Chi","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Guangdong Medical University & Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University Zhanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guan\u2010Qiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Hainan General Hospital (Hainan Affiliated Hospital of Medical University) Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Huan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Centre for Cancer Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Centre Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1402-8963","authenticated-orcid":false,"given":"Zhen\u2010Yu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Centre for Cancer Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Centre Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"437","article-title":"Radiation therapy\u2010associated toxicity: etiology, management, and prevention","volume":"71","author":"Wang K","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/S0140-6736(24)02319-5","article-title":"Radiotherapy toxicities: mechanisms, management, and future directions","volume":"405","author":"Verginadis II","year":"2025","journal-title":"Lancet"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa1209825","article-title":"Risk of ischemic 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Am Coll Cardiol"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1161\/CIRCRESAHA.124.325402","article-title":"Cardiac fibrosis in the multi\u2010omics era: implications for heart failure","volume":"136","author":"Ghazal R","year":"2025","journal-title":"Circ Res"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/s41580-024-00716-0","article-title":"Fibroblast and myofibroblast activation in normal tissue repair and fibrosis","volume":"25","author":"Younesi FS","year":"2024","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s11886-023-01877-8","article-title":"Fibroblast and immune cell cross\u2010talk in cardiac fibrosis","volume":"25","author":"Hara A","year":"2023","journal-title":"Curr Cardiol Rep"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41392-024-01840-1","article-title":"Macrophages in 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