{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T07:32:12Z","timestamp":1793345532295,"version":"4.5.0"},"reference-count":51,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":21,"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"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp; Disease"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Obesity impairs endothelial nitric oxide synthase (eNOS)\u2010nitric oxide (NO) signaling, triggering chronic inflammation, endothelial dysfunction and defective vasodilation, which drives cardiometabolic diseases. Existing metabolic therapies provide only indirect vascular protection and fail to resolve residual inflammatory\u2010mediated cardiovascular risk. As an anti\u2010inflammatory interleukin 12 (IL\u201012) family cytokine, interleukin 35 (IL\u201035) is suppressed in obesity and exerts vascular protective effects under inflammatory conditions, yet its function and underlying mechanisms in obesity\u2011related endothelial vasodilator dysfunction remain undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>An obese mouse model was established by 8\u2010week high\u2010fat diet (HFD) feeding, followed by 4\u2010week intraperitoneal administration of recombinant mouse IL\u201035. Aortic\u2010ring assays evaluated vasodilatory function. Palmitic acid (PA)\u2010treated human umbilical vein endothelial cells (HUVECs), recapitulate lipotoxic endothelial injury, were treated with recombinant human IL\u201035. Western blotting, immunofluorescence, 4\u2010amino\u20105\u2010methylamino\u20102\u2032,7\u2032\u2010difluorofluorescein diacetate (DAF\u2010FM DA) detection and immunoprecipitation\u2010mass spectrometry (IP\u2010MS) were applied to detect IL\u201035\u2010subunit (Epstein\u2010Barr virus\u2010induced gene 3 [EBI3] and interleukin\u201012 subunit alpha [IL\u201012A]) levels, eNOS Ser1177 phosphorylation, phosphorylation of mitogen\u2010activated protein kinase\/extracellular signal\u2010regulated kinase (MAPK\/ERK) signaling molecules (cellular rapidly accelerated fibrosarcoma [cRAF], mitogen\u2010activated protein kinase kinase [MEK], and ERK) and signal transducer and activator of transcription 3 (STAT3) activation, NO production, and eNOS\u2010binding partners. Rescue assays were performed using Raf or ERK specific inhibitors and STAT3 small interfering RNA (siRNA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HFD mice displayed reduced aortic endothelial EBI3 expression, impaired endothelium\u2010dependent vasorelaxation, decreased eNOS Ser1177 phosphorylation and lowered NO production; all these phenotypes were rescued by exogenous IL\u201035. IP\u2010MS and immunoblotting demonstrated that IL\u201035 strengthened eNOS\u2010ERK1 interaction and restored PA\u2010repressed phosphorylation of cRAF, MEK, ERK and eNOS Ser1177, which were abrogated by Raf or ERK blockade. Furthermore, IL\u201035 recovered STAT3 phosphorylation suppressed by PA, while STAT3 knockdown blunted IL\u201035\u2010driven MAPK\/ERK activation, eNOS phosphorylation and subsequent NO production.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IL\u201035 alleviates obesity\u2010induced impairment of endothelium\u2010dependent vasodilation via the STAT3\u2010MAPK\/ERK\u2010eNOS axis, which elevates eNOS Ser1177 phosphorylation and NO synthesis. This work supports IL\u201035 as a prospective therapeutic candidate for obesity\u2010associated vascular complications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/iid3.70564","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:30:14Z","timestamp":1792672214000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin\u201035 Ameliorates Obesity\u2010Associated Impairment of Endothelium\u2010Dependent Vasodilation via the STAT3\u2010MAPK\/ERK\u2010eNOS Signaling Axis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3211-3674","authenticated-orcid":false,"given":"Kai","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang China"},{"name":"Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8729-650X","authenticated-orcid":false,"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang China"},{"name":"Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0411-0468","authenticated-orcid":false,"given":"Ren","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang China"},{"name":"Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4795-767X","authenticated-orcid":false,"given":"Yunman","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang China"},{"name":"Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0981-3910","authenticated-orcid":false,"given":"Yanqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang China"},{"name":"Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","unstructured":"Worldwide Trends in Underweight and Obesity From 1990 to 2022: A Pooled Analysis of 3663 Population\u2010Representative Studies With 222 Million Children Adolescents and Adults. 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