HDAC11-Driven STAT3 Activation Modulates Epigenetic Regulation, Promoting Pro-Inflammatory Cytokine Production and Endothelial Dysfunction in Diabetes

HDAC11-Driven STAT3 Activation Modulates Epigenetic Regulation, Promoting Pro-Inflammatory Cytokine Production and Endothelial Dysfunction in Diabetes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article HDAC11-Driven STAT3 Activation Modulates Epigenetic Regulation, Promoting Pro-Inflammatory Cytokine Production and Endothelial Dysfunction in Diabetes Andriana Margariti, Wiwit Ananda Wahyu Setyaningsih, Hojjat Naderi-Meshkin, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6837535/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Diabetes mellitus is marked by chronic low-grade inflammation, increasing the risk of infections and vascular complications. In this study, we uncover a novel link between bacterial infection and epigenetic regulation in diabetes. We found that infection with Escherichia coli strongly induces the expression of histone deacetylase 11 (HDAC11) in endothelial cell-derived induced pluripotent stem cells (iPS-ECs) from diabetic donors. This upregulation of HDAC11 correlated with a surge in pro-inflammatory cytokine production and marked endothelial dysfunction. Strikingly, treatment with an HDAC11-specific inhibitor significantly dampened inflammatory signaling and restored endothelial function, pointing to a potential therapeutic strategy. Further mechanistic insights revealed a direct interaction between HDAC11 and STAT3, a key regulator of inflammatory gene expression. These findings position HDAC11 as a critical mediator of infection-induced vascular inflammation in diabetes and highlight it as a promising epigenetic target to combat endothelial damage and improve vascular health in diabetic patients. Health sciences/Molecular medicine Biological sciences/Cell biology diabetes vascular inflammaNon epigeneNc memory iPS-ECs HDAC11 STAT3 infecNons Full Text Additional Declarations Yes there is potential Competing Interest. AM declared a stock ownership in ReproGO (University spinout). AWS declared honoraria as Editor in Chief for an Elsevier journal and stock ownership in Vascversa and Medinect (University spinouts). The rest of the authors declare no competing interests. Supplementary Files SupplementaryFiguresHDAC1104062514.15PM.pdf Supplementary figure 1-6 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6837535","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":486740726,"identity":"276d8f73-76f0-4f40-bc23-84b44668e723","order_by":0,"name":"Andriana Margariti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYDADNgbGxgcMDAfAHMYGorSwMTYbkKYFaA2bBFFa+Bu4Ez9X/LLL55Nvbqt423aHgb/9AJvkDDxaJA7wbpY825ds2cbG2HZzbtszBokzCWySG/C55wDvBsnGHmYDoF/abvO2HWZguMHAJvkAjw55oC0/G3vqwVqKQVrkCWkxOMC7TbLhx2GwFmaQFgOQFnwOMzzMu82yseE4UEtis+Scc894DM8kNlvi877c8d7NNxv+VBvINx9/+OFN2R05ueOHD97swed9ZiBmbINyeMCIqIj8g9AyCkbBKBgFowADAACO7UybzjdOqwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9303-8371","institution":"Queen's University Belfast","correspondingAuthor":true,"prefix":"","firstName":"Andriana","middleName":"","lastName":"Margariti","suffix":""},{"id":486740727,"identity":"9dfa33df-1835-410d-981d-0b97fa0f4aaf","order_by":1,"name":"Wiwit Ananda Wahyu Setyaningsih","email":"","orcid":"https://orcid.org/0000-0002-4334-5012","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wiwit","middleName":"Ananda Wahyu","lastName":"Setyaningsih","suffix":""},{"id":486740728,"identity":"606b9ab0-1354-41e4-8df6-64ad3ff26b1c","order_by":2,"name":"Hojjat Naderi-Meshkin","email":"","orcid":"https://orcid.org/0000-0003-3988-3229","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Hojjat","middleName":"","lastName":"Naderi-Meshkin","suffix":""},{"id":486740729,"identity":"c5dd4d3d-ff3c-4f33-be1e-08bf7b26b3bc","order_by":3,"name":"Andrew Yacoub","email":"","orcid":"https://orcid.org/0000-0002-8780-3484","institution":"Queen’s University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Yacoub","suffix":""},{"id":486740730,"identity":"ce58c10a-3810-4cc6-b66e-1b07017a7853","order_by":4,"name":"Victoria A Cornelius","email":"","orcid":"","institution":"Queen’s University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Victoria","middleName":"A","lastName":"Cornelius","suffix":""},{"id":486740731,"identity":"7784eca9-bd2b-4dbc-aedc-aaddde7162c5","order_by":5,"name":"Johnatas Dutra Silva","email":"","orcid":"","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Johnatas","middleName":"Dutra","lastName":"Silva","suffix":""},{"id":486740732,"identity":"2b99b5b4-2722-46fa-8551-3a05c704198b","order_by":6,"name":"Akbar Satria Fitriawan","email":"","orcid":"","institution":"Department of Nursing, Faculty of Health Sciences, Universitas Respati Yogyakarta, Yogyakarta 55282, Indonesia.","correspondingAuthor":false,"prefix":"","firstName":"Akbar","middleName":"Satria","lastName":"Fitriawan","suffix":""},{"id":486740733,"identity":"1cafc1b0-b2f5-473f-be0b-68b05c978e81","order_by":7,"name":"Jasenka Gudurich-Fuchs","email":"","orcid":"","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jasenka","middleName":"","lastName":"Gudurich-Fuchs","suffix":""},{"id":486740734,"identity":"7cbcaddb-ee35-4b1b-86c4-bc8456d44891","order_by":8,"name":"Asim Jamalabdalnaser A. Tashkandi","email":"","orcid":"","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Asim","middleName":"Jamalabdalnaser A.","lastName":"Tashkandi","suffix":""},{"id":486740735,"identity":"cea62b1b-1237-4a06-b14f-17eb7efcfc78","order_by":9,"name":"Refik Kuburas","email":"","orcid":"","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Refik","middleName":"","lastName":"Kuburas","suffix":""},{"id":486740736,"identity":"f0716969-98d6-4f60-b766-137b7436129c","order_by":10,"name":"Anna Zampetaki","email":"","orcid":"https://orcid.org/0000-0002-7257-8624","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Zampetaki","suffix":""},{"id":486740737,"identity":"8656939b-b4e6-4c38-8362-891b5e263753","order_by":11,"name":"Noemi Lois","email":"","orcid":"https://orcid.org/0000-0003-2666-2937","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Noemi","middleName":"","lastName":"Lois","suffix":""},{"id":486740738,"identity":"6477dabf-7662-4e07-8c8f-bac463d36fdb","order_by":12,"name":"Alan Stitt","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Alan","middleName":"","lastName":"Stitt","suffix":""},{"id":486740739,"identity":"3b796302-89e7-43fa-820c-89d802ea1f7a","order_by":13,"name":"Miguel A. Valvano","email":"","orcid":"https://orcid.org/0000-0001-8229-3641","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Miguel","middleName":"A.","lastName":"Valvano","suffix":""},{"id":486740740,"identity":"545e3d6d-38e6-4957-bc6e-9100e638c356","order_by":14,"name":"David Grieve","email":"","orcid":"https://orcid.org/0000-0002-3655-7754","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Grieve","suffix":""},{"id":486740741,"identity":"6a5adfcd-4ef9-4e78-beec-39df2e4592c1","order_by":15,"name":"Yaser Atlasi","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Yaser","middleName":"","lastName":"Atlasi","suffix":""},{"id":486740742,"identity":"35c02b49-3d3b-4cf8-9ca3-5f89f279e810","order_by":16,"name":"Anna Krasnodembskaya","email":"","orcid":"https://orcid.org/0000-0002-2380-5069","institution":"Queen's University Belfast, The Wellcome-Wolfson Institute for Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Krasnodembskaya","suffix":""}],"badges":[],"createdAt":"2025-06-06 13:41:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6837535/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6837535/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87156433,"identity":"798d3d29-46e3-4e37-a1ca-2afe7b120baf","added_by":"auto","created_at":"2025-07-21 03:22:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3970835,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptHDAC11060625.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6837535/v1_covered_76ad3460-6c1a-45b1-a6fc-49a1c17903a7.pdf"},{"id":87156048,"identity":"ec60e149-f6bb-472c-b8a9-8cecf4c70ada","added_by":"auto","created_at":"2025-07-21 03:14:10","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3328520,"visible":true,"origin":"","legend":"Supplementary figure 1-6","description":"","filename":"SupplementaryFiguresHDAC1104062514.15PM.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6837535/v1/2310e0694326da9c820880d0.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nAM declared a stock ownership in ReproGO (University spinout). AWS declared honoraria as Editor in Chief for an Elsevier journal and stock ownership in Vascversa and Medinect (University spinouts). The rest of the authors declare no competing interests.","formattedTitle":"HDAC11-Driven STAT3 Activation Modulates Epigenetic Regulation, Promoting Pro-Inflammatory Cytokine Production and Endothelial Dysfunction in Diabetes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"diabetes, vascular inflammaNon, epigeneNc memory, iPS-ECs, HDAC11, STAT3, infecNons","lastPublishedDoi":"10.21203/rs.3.rs-6837535/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6837535/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Diabetes mellitus is marked by chronic low-grade inflammation, increasing the risk of infections and vascular complications. In this study, we uncover a novel link between bacterial infection and epigenetic regulation in diabetes.\r\n\r\nWe found that infection with Escherichia coli strongly induces the expression of histone deacetylase 11 (HDAC11) in endothelial cell-derived induced pluripotent stem cells (iPS-ECs) from diabetic donors. This upregulation of HDAC11 correlated with a surge in pro-inflammatory cytokine production and marked endothelial dysfunction.\r\n\r\nStrikingly, treatment with an HDAC11-specific inhibitor significantly dampened inflammatory signaling and restored endothelial function, pointing to a potential therapeutic strategy. Further mechanistic insights revealed a direct interaction between HDAC11 and STAT3, a key regulator of inflammatory gene expression.\r\n\r\nThese findings position HDAC11 as a critical mediator of infection-induced vascular inflammation in diabetes and highlight it as a promising epigenetic target to combat endothelial damage and improve vascular health in diabetic patients.","manuscriptTitle":"HDAC11-Driven STAT3 Activation Modulates Epigenetic Regulation, Promoting Pro-Inflammatory Cytokine Production and Endothelial Dysfunction in Diabetes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-21 03:14:05","doi":"10.21203/rs.3.rs-6837535/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3b6a7b0a-037c-45b9-aff4-3e0d675f2987","owner":[],"postedDate":"July 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51673529,"name":"Health sciences/Molecular medicine"},{"id":51673530,"name":"Biological sciences/Cell biology"}],"tags":[],"updatedAt":"2025-07-21T03:14:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-21 03:14:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6837535","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6837535","identity":"rs-6837535","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}