{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:55:00Z","timestamp":1785434100636,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Clinical Projects of Peking University Third Hospital","award":["BYSYZD2025007"],"award-info":[{"award-number":["BYSYZD2025007"]}]},{"award":["BYSYZD2025007"],"award-info":[{"award-number":["BYSYZD2025007"]}],"id":[{"id":"https:\/\/ror.org\/04wwqze12","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071308"],"award-info":[{"award-number":["82071308"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82071308"],"award-info":[{"award-number":["82071308"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carotid body tumors (CBTs) exhibit pronounced clinical heterogeneity, particularly in fibrotic progression, yet the underlying cellular mechanisms remain poorly defined. Here, we performed single-cell RNA sequencing on 64,944 cells from three fibrotic CBT (FCBT) and three non-fibrotic CBT (nFCBT) specimens to construct a high-resolution cellular atlas of CBT fibrosis. Integrated analyses revealed that FCBTs are distinguished by a FOXP2+ chief cell subpopulation exhibiting a metabolic shift toward mitochondrial respiration and enhanced MIF signaling, which may facilitate macrophage recruitment. Endothelial cells expanded in FCBTs and acquired pro-angiogenic signatures driven by macrophage-derived CXCL signaling. Notably, CXCL14+ fibroblasts emerged as the principal effectors of extracellular matrix deposition, with lineage inference suggesting their origin from smooth muscle cells. Immune cells, including T\/NK and mast cells, further modulated the fibrotic niche through cytokine interactions. This study provides the first comprehensive single-cell dissection of CBT fibrosis, identifies FOXP2+ chief cells as initiators of stromal remodeling, and highlights CXCL14+ fibroblasts as key matrix-producing effectors. These findings nominate FOXP2 and CXCL14 as potential therapeutic targets for mitigating fibrosis in CBT patients.<\/jats:p>","DOI":"10.3390\/ijms27135750","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:49:23Z","timestamp":1782434963000},"page":"5750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXP2+ Chief Cells and CXCL14+ Fibroblasts Drive Fibrotic Remodeling in Carotid Body Tumors"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6323-001X","authenticated-orcid":false,"given":"Kangxi","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7700-8664","authenticated-orcid":false,"given":"Jiazhi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangnan","family":"Ao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongli","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongzheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6454-0706","authenticated-orcid":false,"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cao, K., Yuan, W., Hou, C., Wang, Z., Yu, J., and Wang, T. (2024). Hypoxic Signaling Pathways in Carotid Body Tumors. Cancers, 16.","DOI":"10.3390\/cancers16030584"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101555","DOI":"10.1016\/j.suronc.2021.101555","article-title":"Results of resection of carotid body tumors with and without lymphnodes\u2019 dissection","volume":"37","author":"Illuminati","year":"2021","journal-title":"Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e31175","DOI":"10.1002\/jcp.31175","article-title":"Single-cell transcriptome analysis reveals tumoral microenvironment heterogenicity and hypervascularization in human carotid body tumor","volume":"239","author":"Cai","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1097\/RLU.0000000000004870","article-title":"Somatostatin Receptor-Directed PET\/CT Can Differentiate Between Different Subtypes of Head and Neck Paragangliomas","volume":"48","author":"Zhi","year":"2023","journal-title":"Clin. Nucl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.33963\/KP.15709","article-title":"Surgical approach to carotid sinus syndrome and carotid body tumor","volume":"79","author":"Dziekiewicz","year":"2021","journal-title":"Kardiol. Pol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1007\/s00268-023-07068-4","article-title":"Study on the Influencing Factors of Short-Term Recovery of Neurological Symptoms after Carotid Body Tumor Resection","volume":"47","author":"Yuan","year":"2023","journal-title":"World J. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/0002-9610(71)90436-3","article-title":"Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases","volume":"122","author":"Shamblin","year":"1971","journal-title":"Am. J. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.jvs.2025.06.003","article-title":"Safety and outcomes of self-expanding covered stents in carotid revascularization for shamblin class III carotid body tumors","volume":"82","author":"Wang","year":"2025","journal-title":"J. Vasc. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.jvs.2024.11.008","article-title":"Preoperative radiological features in predicting complications of carotid body tumor resection","volume":"81","author":"Alanezi","year":"2025","journal-title":"J. Vasc. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10777","DOI":"10.2147\/JIR.S541656","article-title":"Advances in cGAS-STING Signaling in Fibrosis Diseases: Therapeutic Target in Pathological Scars","volume":"18","author":"Zhao","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zeng, H., Singh, P., Sinha, R., Stephens, C.T., Ahmad, A., Athar, M., and Antony, V.B. (2025). Inhibition of BRD4 prevents peribronchial fibrosis in mice with cutaneous lewisite exposure. Front. Mol. Biosci., 12.","DOI":"10.3389\/fmolb.2025.1644792"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.jare.2025.08.014","article-title":"Airway basal stem cell-derived extracellular vesicles drive ECM remodeling and suppress fibroblasts activation via the miR-30a-5p\/FAP axis in benign tracheal stenosis","volume":"83","author":"Luo","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1055\/s-0040-1708876","article-title":"Hepatic Stellate Cell-Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis","volume":"40","author":"Matsuda","year":"2020","journal-title":"Semin. Liver Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/hep.27332","article-title":"Hepatic inflammation and fibrosis: Functional links and key pathways","volume":"61","author":"Seki","year":"2015","journal-title":"Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41419-025-07615-y","article-title":"MMP1-induced NF-\u03baB activation promotes epithelial-mesenchymal transition and sacituzumab govitecan resistance in hormone receptor-positive breast cancer","volume":"16","author":"Chen","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.schres.2025.07.002","article-title":"Young first-episode psychosis patients exhibit impaired microvascular function in the skin and low systemic nitric oxide availability, independent of classical cardiovascular risk factors","volume":"283","author":"Marczyk","year":"2025","journal-title":"Schizophr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s12964-025-02120-3","article-title":"IL-1\u03b2 stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes","volume":"23","author":"Cao","year":"2025","journal-title":"Cell Commun. Signal. CCS"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s40104-025-01247-0","article-title":"Dietary inulin supplementation in early gestation regulates uterine fluid exosomes and angiogenesis to improve embryo implantation in sows","volume":"16","author":"Chang","year":"2025","journal-title":"J. Anim. Sci. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kudryavtseva, A.V., Lukyanova, E.N., Kalinin, D.V., Zaretsky, A.R., Pokrovsky, A.V., Golovyuk, A.L., Fedorova, M.S., Pudova, E.A., Kharitonov, S.L., and Pavlov, V.S. (2019). Mutational load in carotid body tumor. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0483-x"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Celada, L., Cubiella, T., San-Juan-Guardado, J., San Jos\u00e9 Mart\u00ednez, A., Vald\u00e9s, N., Jim\u00e9nez-Fonseca, P., D\u00edaz, I., Enguita, J.M., Astudillo, A., and \u00c1lvarez-Gonz\u00e1lez, E. (2022). Differential HIF2\u03b1 Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions. Cancers, 14.","DOI":"10.3390\/cancers14122986"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.1210\/jc.2018-01471","article-title":"Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas\/Paragangliomas Associated With SDHB Mutations","volume":"104","author":"Celada","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jdermsci.2020.06.002","article-title":"Application of single-cell RNA sequencing on human skin: Technical evolution and challenges","volume":"99","author":"Kim","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/s41587-020-0469-4","article-title":"Benchmarking single-cell RNA-sequencing protocols for cell atlas projects","volume":"38","author":"Mereu","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41581-018-0021-7","article-title":"Single-cell RNA sequencing for the study of development, physiology and disease","volume":"14","author":"Potter","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nri.2017.76","article-title":"Single-cell RNA sequencing to explore immune cell heterogeneity","volume":"18","author":"Papalexi","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1172\/JCI28338","article-title":"PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells","volume":"117","author":"Foubert","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chen, B., Huan, L., Lu, J., and Yuan, J. (2025). Shapley additive explanations based feature selection reveals CXCL14 as a key immune-related gene in predicting idiopathic pulmonary fibrosis. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1608078"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1053\/j.gastro.2023.07.014","article-title":"Stricturing Crohn\u2019s Disease Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity and Intercellular Interactions","volume":"165","author":"Mukherjee","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e70281","DOI":"10.1002\/ctm2.70281","article-title":"Transitional CXCL14(+) cancer-associated fibroblasts enhance tumour metastasis and confer resistance to EGFR-TKIs, revealing therapeutic vulnerability to filgotinib in lung adenocarcinoma","volume":"15","author":"Xu","year":"2025","journal-title":"Clin. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5750\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:28:24Z","timestamp":1783398504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":29,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135750"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135750","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}