Clemastine fumarate activates lipophagy to promote oligodendrocyte progenitor cells differentiation and remyelination in a cuprizone-induced demyelination model

Clemastine fumarate activates lipophagy to promote oligodendrocyte progenitor cells differentiation and remyelination in a cuprizone-induced demyelination model | 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 Clemastine fumarate activates lipophagy to promote oligodendrocyte progenitor cells differentiation and remyelination in a cuprizone-induced demyelination model Xing Li, Wenyue Li, Qingqing Sun, Jiayi He, Wanlin Liao, Xiaowen Li, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9080570/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Background: Remyelination failure in multiple sclerosis (MS) is associated with impaired oligodendrocyte progenitor cell (OPC) differentiation. Our previous studies showed OPCs phagocytose myelin debris, causing intracellular lipid accumulation that may block differentiation. However, the metabolic consequences of this lipid overload remain unclear. Clemastine fumarate promotes remyelination via muscarinic receptor antagonism, but its role in OPC lipid metabolism is unknown. Objective: To investigate whether clemastine fumarate alleviates lipid droplet (LD) accumulation in OPCs by activating lipophagy, supporting their differentiation and remyelination. Methods: In vitro, primary OPCs and Oli-neu cells were treated with myelin debris; in vivo, a cuprizone-induced demyelination model was used. Outcomes were assessed by immunohistochemistry, fluorescence staining, and RNA sequencing. Results: Clemastine fumarate enhanced OPC differentiation and promoted myelin debris and LD clearance in vitro, upregulating BECN1 and autophagy pathways. In cuprizone mice, it improved myelin integrity, promoted OPC maturation, and reduced LD accumulation and p62 expression. Conclusion: This study reveals a novel mechanism: clemastine fumarate can promote remyelination by activating lipophagy to clear pathological LDs in OPCs. Biological sciences/Neuroscience/Myelin biology and repair Biological sciences/Neuroscience/Diseases of the nervous system Clemastine fumarate Oligodendrocyte progenitor cell Myelin debris Lipophagy Demyelinating disease Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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. 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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-9080570","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":609207486,"identity":"d3876763-1bf2-4d9d-b542-f058a0523068","order_by":0,"name":"Xing 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model","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Clemastine fumarate, Oligodendrocyte progenitor cell, Myelin debris, Lipophagy, Demyelinating disease","lastPublishedDoi":"10.21203/rs.3.rs-9080570/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9080570/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Remyelination failure in multiple sclerosis (MS) is associated with impaired oligodendrocyte progenitor cell (OPC) differentiation. Our previous studies showed OPCs phagocytose myelin debris, causing intracellular lipid accumulation that may block differentiation. However, the metabolic consequences of this lipid overload remain unclear. Clemastine fumarate promotes remyelination via muscarinic receptor antagonism, but its role in OPC lipid metabolism is unknown.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To investigate whether clemastine fumarate alleviates lipid droplet (LD) accumulation in OPCs by activating lipophagy, supporting their differentiation and remyelination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In vitro, primary OPCs and Oli-neu cells were treated with myelin debris; in vivo, a cuprizone-induced demyelination model was used. Outcomes were assessed by immunohistochemistry, fluorescence staining, and RNA sequencing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Clemastine fumarate enhanced OPC differentiation and promoted myelin debris and LD clearance in vitro, upregulating BECN1 and autophagy pathways. In cuprizone mice, it improved myelin integrity, promoted OPC maturation, and reduced LD accumulation and p62 expression.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This study reveals a novel mechanism: clemastine fumarate can promote remyelination by activating lipophagy to clear pathological LDs in OPCs.\u003c/p\u003e","manuscriptTitle":"Clemastine fumarate activates lipophagy to promote oligodendrocyte progenitor cells differentiation and remyelination in a cuprizone-induced demyelination model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 08:50:53","doi":"10.21203/rs.3.rs-9080570/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-biology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsbio","sideBox":"Learn more about [Communications Biology](http://www.nature.com/commsbio/)","snPcode":"","submissionUrl":"","title":"Communications Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"cf2e28bb-268a-419f-9ab1-f192e97c12e0","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64823850,"name":"Biological sciences/Neuroscience/Myelin biology and repair"},{"id":64823851,"name":"Biological sciences/Neuroscience/Diseases of the nervous system"}],"tags":[],"updatedAt":"2026-04-07T15:57:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 08:50:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9080570","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9080570","identity":"rs-9080570","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}