Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in senescent cells

Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in senescent cells | 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 Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in senescent cells David Soriano-Castell, Marie Goujon, Nawab Dar, Antonio Currais, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8117957/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 Cellular senescence, a complex biological process characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype, has emerged as a critical target for therapeutic development for age-related diseases. Ferroptosis, an iron-dependent regulated cell death pathway driven by the accumulation of lipid peroxidation in cell membranes, has been implicated in neurodegenerative diseases and other age-related disorders. This study investigated the relationship between cellular senescence and ferroptosis. Using human fetal lung Wi-38 fibroblasts induced to senesce via replicative exhaustion, we report a novel role for acid ceramidase (ACase), which breaks down ceramides into sphingosine and free fatty acids, in regulating the sensitivity of senescent cells to lipid peroxidation and ferroptosis through the modulation of polyunsaturated fatty acid composition of membrane phospholipids. Furthermore, we demonstrate a cell non-autonomous paracrine sensitization of non-senescent cells to ferroptosis by senescent cells. Together, these findings unveil ACase as a novel regulator of the ferroptosis pathway and open promising therapeutic avenues for targeting senescence-linked disorders and advancing healthy aging strategies. Biological sciences/Cell biology/Senescence Biological sciences/Biochemistry/Lipidomics 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. We do this by developing innovative software and high quality services for the global research community. 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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-8117957","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":548739837,"identity":"da17a003-ff55-42f8-bd23-998665524c48","order_by":0,"name":"David Soriano-Castell","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIie3QsYrCMBjA8S8ITnJd42D7CilZDvRhEoTr0oMbHRx6BHQRu+rkK/QRegTqUnDNcEO76HJDp8NBxM/lkONy6uaQP5S00F/4EgCX6xHL8RE/X2/PPkBL4VvrJkISYJTjegOBCyKTa+Rpo4umGn/63nS9qxpGo9X0QzEY9dH+Xde8DBei2HJaxuH7gtHXrJRKQBlZCTMdDqKtZQYxUZ0zAalyMtF2simRHJF4u1odcLAgrZEc/yF5zEHinhkVocLjCzA4GEns5HwWkHPNqfkKlzNGw8zUioki4jaCN6bJ/lv7XhpVzX40CIJ0qGkz7vdsxJK473eXy+Vy/eoE1IthGAqkaMsAAAAASUVORK5CYII=","orcid":"","institution":"The Salk Institute for Biological Studies","correspondingAuthor":true,"prefix":"","firstName":"David","middleName":"","lastName":"Soriano-Castell","suffix":""},{"id":548739838,"identity":"c0009949-02cf-49a5-9a06-7dc572e70286","order_by":1,"name":"Marie Goujon","email":"","orcid":"","institution":"The Salk Institute for Biological Studies","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Goujon","suffix":""},{"id":548739839,"identity":"aafe7195-5a3c-4b72-ab19-f0e8c36b74f7","order_by":2,"name":"Nawab Dar","email":"","orcid":"","institution":"The Salk Institute for Biological Studies","correspondingAuthor":false,"prefix":"","firstName":"Nawab","middleName":"","lastName":"Dar","suffix":""},{"id":548739840,"identity":"c4650bfb-02bf-44fb-a5ef-341ac1279c19","order_by":3,"name":"Antonio Currais","email":"","orcid":"","institution":"Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Currais","suffix":""},{"id":548739841,"identity":"4f2ee166-84d5-4c03-a0dc-6bb79fdbbbe3","order_by":4,"name":"Pamela Maher","email":"","orcid":"","institution":"The Salk Institute for Biological Studies","correspondingAuthor":false,"prefix":"","firstName":"Pamela","middleName":"","lastName":"Maher","suffix":""}],"badges":[],"createdAt":"2025-11-14 20:10:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8117957/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8117957/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99797974,"identity":"caa88b6e-800a-4c7d-978b-f38e203fdd6f","added_by":"auto","created_at":"2026-01-08 13:47:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1007168,"visible":true,"origin":"","legend":"Article File","description":"","filename":"SorianoCastellManuscriptFigs.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8117957/v1_covered_23a40b7f-8316-444b-b636-7496a63a0ac5.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in senescent cells","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":"cell-death-and-disease","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cddis","sideBox":"Learn more about [Cell Death \u0026 Disease](http://www.nature.com/cddis/)","snPcode":"41419","submissionUrl":"https://mts-cddis.nature.com/cgi-bin/main.plex","title":"Cell Death \u0026 Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8117957/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8117957/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Cellular senescence, a complex biological process characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype, has emerged as a critical target for therapeutic development for age-related diseases. 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