Sodium Butyrate Ameliorates Diabetic Kidney Disease Partially Through ACSS2/P300-Mediated Histone Butyrylation Pathway

Sodium Butyrate Ameliorates Diabetic Kidney Disease Partially Through ACSS2/P300-Mediated Histone Butyrylation Pathway | 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 Research Article Sodium Butyrate Ameliorates Diabetic Kidney Disease Partially Through ACSS2/P300-Mediated Histone Butyrylation Pathway Xi Cheng, Tingting Zhou, Kang Geng, Yulin Mou, Yanqiu He, Butuo Xu, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7519371/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 Background: Studies suggest that sodium butyrate (NaB) can ameliorate glucose and lipid metabolism, as well as renal damage in dabetic kidney disease (DKD) mice, potentially through histone post-translational modifications. Histone butyrylation, an acylation modification induced by butyrate, is facilitated by acetyl-CoA synthetase 2 (ACSS2) and P300. However, the precise role and mechanism of NaB and histone butyrylation in DKD prevention and treatment remain unclear. Purpose: This study aimed to investigate whether NaB improves renal inflammation and fibrosis in DKD through the ACSS2/P300-mediated histone butyrylation pathway. Methods: DKD models were replicated in vivo and in vitro using db/db mice and high glucose-induced mesangial cells, respectively. Intervention methods included NaB/butyryl-CoA, ACSS2 inhibitor/siRNA, adeno-associated virus 9 (AAV9)-mediated ACSS2 overexpression, and A485 (a P300 inhibitor). Assessments included body weight, glucose levels, lipid profile, urinary albumin-to-creatinine ratio (UACR), renal function and pathology, and the expression levels of pan-butyrylation (PanKbu), histone lysine butyrylation (H3K9bu, H3K18bu), and inflammatory and fibrotic cytokines. Results: NaB exhibited antidiabetic effects, reduced serum lipid levels, alleviated UACR, and improved renal function, reducing inflammatory and fibrotic damage in the kidneys of db/db mice. Additionally, PanKbu, H3K9bu, and H3K18bu in kidney tissues of DKD mice and high-glucose-induced mesangial cells were upregulated by NaB or butyryl-CoA in a concentration-dependent manner. Mechanistically, ACSS2 inhibition or knockdown by siRNA hindered, while ACSS2 overexpression facilitated, NaB-induced histone butyrylation and its anti-inflammatory and anti-fibrotic effects. Lastly, A485 re详versed the renal protective effects induced by NaB or butyryl-CoA. Conclusions: This study identifies a novel role for NaB in alleviating DKD and inhibiting the expression of inflammatory and fibrotic genes partially through the ACSS2 and P300-mediated histone butyrylation pathway, suggesting that histone butyrylation may play a significant role in the pathogenesis and treatment of DKD. Diabetic kidney disease Sodium butyrate Histone butyrylation Acetyl-CoA synthetase 2 P300 Full Text Additional Declarations No competing interests reported. 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-7519371","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512821441,"identity":"122c2c0a-84b2-41fe-b563-a012e2b7e38e","order_by":0,"name":"Xi Cheng","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Cheng","suffix":""},{"id":512821442,"identity":"3fdaf98c-e089-40da-b254-a06873b596e5","order_by":1,"name":"Tingting Zhou","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Zhou","suffix":""},{"id":512821443,"identity":"3862da30-15af-4609-b229-48d06973f490","order_by":2,"name":"Kang Geng","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kang","middleName":"","lastName":"Geng","suffix":""},{"id":512821444,"identity":"f2e5bcc8-5700-402b-b1b2-51af6be170f6","order_by":3,"name":"Yulin Mou","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yulin","middleName":"","lastName":"Mou","suffix":""},{"id":512821445,"identity":"20f57f59-642f-48ff-8347-67040860ae33","order_by":4,"name":"Yanqiu He","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanqiu","middleName":"","lastName":"He","suffix":""},{"id":512821446,"identity":"3498b57a-c16f-4005-8120-c386d80e109b","order_by":5,"name":"Butuo Xu","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Butuo","middleName":"","lastName":"Xu","suffix":""},{"id":512821447,"identity":"1f949778-1bc5-4ab7-8d12-86aa542919cc","order_by":6,"name":"Qian Ren","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Ren","suffix":""},{"id":512821448,"identity":"5577d531-ef4b-46a7-bfab-363a93d5d6cd","order_by":7,"name":"Dongze Li","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dongze","middleName":"","lastName":"Li","suffix":""},{"id":512821449,"identity":"a780d881-003f-4183-9cef-ab984f3ef354","order_by":8,"name":"Jidi Wu","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jidi","middleName":"","lastName":"Wu","suffix":""},{"id":512821450,"identity":"0a3de687-d9ed-4463-9ad3-d1121017f082","order_by":9,"name":"Yang Long","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Long","suffix":""},{"id":512821452,"identity":"88ce4c05-38ce-4d35-b51d-3a675233757d","order_by":10,"name":"Man Guo","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Guo","suffix":""},{"id":512821453,"identity":"18586c1e-93b9-4c23-81cd-aef8a6151c9a","order_by":11,"name":"Qin Wan","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Wan","suffix":""},{"id":512821454,"identity":"804a8418-6a73-4131-95ec-8700d6d856ba","order_by":12,"name":"Chenlin Gao","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chenlin","middleName":"","lastName":"Gao","suffix":""},{"id":512821456,"identity":"fab817fc-80ee-48e3-baaf-bd4799112899","order_by":13,"name":"Yong Xu","email":"","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Xu","suffix":""},{"id":512821458,"identity":"6959cc76-8787-4424-96cb-31fbe4747c26","order_by":14,"name":"Wei Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIie3Qv0rEMBzA8YRCbvlxc0rO6ytUCncIRX2UHAfNouAkHVsK6XIP0EnfonNKBpc8gOCiCN7icoOS6bwITkLbGwXzXQLh9yF/EPL5/mDxzwpkUpavNqdzMqnVcWQKukqQSZMpGH4UQXMqJMMyW93Ry3hIoCVdv718yHRG0KpgN0QLSRFHNm97yVmTLZMTmQFBXZE0oK8lKxXemKf+iz3yBQtbDQSXBQfqyEzxAMshIj4d+QIS4EJBrAWhPB4hV4tw1yog7pgKeMbHiXm/ZXi/BgK4wo1KT6X75G7wLQ+iDa05v4jut1u729Moquvu2eb95LsAfu+owXkXtmMTPp/P9787AC1sWFjf1vnZAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2025-09-02 15:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7519371/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7519371/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98441753,"identity":"7a5b4bb9-03a6-4014-8fb6-d3bee3e7ceee","added_by":"auto","created_at":"2025-12-17 17:05:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5423807,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript0904.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7519371/v1_covered_d92c9c01-b777-48a8-96da-688ef8a8f6e2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sodium Butyrate Ameliorates Diabetic Kidney Disease Partially Through ACSS2/P300-Mediated Histone Butyrylation Pathway","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Diabetic kidney disease, Sodium butyrate, Histone butyrylation, Acetyl-CoA synthetase 2, P300","lastPublishedDoi":"10.21203/rs.3.rs-7519371/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7519371/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Studies suggest that sodium butyrate (NaB) can ameliorate glucose and lipid metabolism, as well as renal damage in dabetic kidney disease (DKD) mice, potentially through histone post-translational modifications. Histone butyrylation, an acylation modification induced by butyrate, is facilitated by acetyl-CoA synthetase 2 (ACSS2) and P300. However, the precise role and mechanism of NaB and histone butyrylation in DKD prevention and treatment remain unclear.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePurpose: This study aimed to investigate whether NaB improves renal inflammation and fibrosis in DKD through the ACSS2/P300-mediated histone butyrylation pathway.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: DKD models were replicated in vivo and in vitro using db/db mice and high glucose-induced mesangial cells, respectively. Intervention methods included NaB/butyryl-CoA, ACSS2 inhibitor/siRNA, adeno-associated virus 9 (AAV9)-mediated ACSS2 overexpression, and A485 (a P300 inhibitor). Assessments included body weight, glucose levels, lipid profile, urinary albumin-to-creatinine ratio (UACR), renal function and pathology, and the expression levels of pan-butyrylation (PanKbu), histone lysine butyrylation (H3K9bu, H3K18bu), and inflammatory and fibrotic cytokines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: NaB exhibited antidiabetic effects, reduced serum lipid levels, alleviated UACR, and improved renal function, reducing inflammatory and fibrotic damage in the kidneys of db/db mice. Additionally, PanKbu, H3K9bu, and H3K18bu in kidney tissues of DKD mice and high-glucose-induced mesangial cells were upregulated by NaB or butyryl-CoA in a concentration-dependent manner. Mechanistically, ACSS2 inhibition or knockdown by siRNA hindered, while ACSS2 overexpression facilitated, NaB-induced histone butyrylation and its anti-inflammatory and anti-fibrotic effects. Lastly, A485 re详versed the renal protective effects induced by NaB or butyryl-CoA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions: This study identifies a novel role for NaB in alleviating DKD and inhibiting the expression of inflammatory and fibrotic genes partially through the ACSS2 and P300-mediated histone butyrylation pathway, suggesting that histone butyrylation may play a significant role in the pathogenesis and treatment of DKD.\u003c/p\u003e","manuscriptTitle":"Sodium Butyrate Ameliorates Diabetic Kidney Disease Partially Through ACSS2/P300-Mediated Histone Butyrylation Pathway","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 17:00:41","doi":"10.21203/rs.3.rs-7519371/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":"e66edf2d-9878-4286-98ae-839a3e0b85ea","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-17T10:53:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-12 17:00:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7519371","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7519371","identity":"rs-7519371","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}