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Bioinformatics analysis revealed that the hub gene (C-X-C motif chemokine ligand 10 [CXCL10]) was predicted to be involved in both endothelial activation and syndecan 4 (SDC4) binding capacity. In both the LPS- and tumor necrosis factor-alpha -induced sepsis models, the expression level and biological function of the hub gene were confirmed by means of quantitative PCR and immunofluorescence staining. With the knockdown of SDC4 and the HS mutation technique, loss-of-function experiments and downstream pathway experiments following modulation of the hub gene\u2019s expression were conducted to elucidate the underlying molecular mechanism. Through the overlap of GSE5883 and the glycosaminoglycan-binding DB, seven genes were discovered to be involved in the biological processes of SDC binding and cytokine\u2013cytokine receptor interactions, including those involving CXCL10. Compared with that in the normal state, the expression of CXCL10 in the ALI state markedly increased during the acute phase of inflammation, and the SDC4 mRNA level greatly increased. Mechanistically, CXCL10 induces a proinflammatory response with the help of SDC4 as a coreceptor, leading to CXCR3\/NF-\u03baB pathway activation and VCAM1 overexpression. This proinflammatory phenotype was further enhanced by knockdown of SDC4. By mutating the heparan sulfate (HS) chain of SDC4, the severity of inflammation was exacerbated, and the recruitment of immune cells was also enhanced. In summary, endothelial-derived SDC4 acts as a negative mediator to ameliorate ALI through modulation of the CXCR3 pathway with the help of HS chains.<\/jats:p>","DOI":"10.1177\/10799907261432941","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:32:39Z","timestamp":1773901959000},"page":"189-203","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Syndecan-4 Acts as a Negative Regulator of the CXCL10\u2013CXCR3 Axis to Attenuate Endothelial Inflammation in Sepsis-Associated ALI"],"prefix":"10.1177","volume":"46","author":[{"given":"Jiayue","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuyi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5575-3833","authenticated-orcid":false,"given":"Zhipeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104736"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10020274"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2014.12.019"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.10.016"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2013.10.010"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-020-06010-9"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-004-3389-4"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2012.04.018"},{"key":"e_1_3_4_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI98322"},{"key":"e_1_3_4_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.115495"},{"key":"e_1_3_4_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e318211ff56"},{"key":"e_1_3_4_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.68.1.729"},{"key":"e_1_3_4_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26154583"},{"key":"e_1_3_4_15_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160647"},{"key":"e_1_3_4_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.7.2528"},{"key":"e_1_3_4_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00483"},{"key":"e_1_3_4_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00919.2007"},{"key":"e_1_3_4_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab295"},{"key":"e_1_3_4_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz289"},{"key":"e_1_3_4_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.21907"},{"key":"e_1_3_4_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13098-024-01431-8"},{"key":"e_1_3_4_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOT.0000000000001135"},{"key":"e_1_3_4_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.124.325855"},{"key":"e_1_3_4_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/pai.13574"},{"key":"e_1_3_4_26_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38644"},{"key":"e_1_3_4_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28237855"},{"key":"e_1_3_4_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-020-00608-1"},{"key":"e_1_3_4_29_1","doi-asserted-by":"publisher","DOI":"10.17219\/acem\/68846"},{"key":"e_1_3_4_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0169100"},{"key":"e_1_3_4_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2008.12.002"},{"issue":"38","key":"e_1_3_4_32_1","doi-asserted-by":"crossref","first-page":"e06209","DOI":"10.1002\/advs.202506209","article-title":"Endothelial\u2010derived CCL7 promotes macrophage polarization and aggravates septic acute lung injury via CCR1\u2010mediated STAT1 succinylation","volume":"12","author":"Li X","year":"2025","unstructured":"Li X, , Long Y, , Zhu Y, et al. 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