Identification of the Lipid Oxygen Radical Defense pathway and its epigenetic control

Identification of the Lipid Oxygen Radical Defense pathway and its epigenetic control | 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 Identification of the Lipid Oxygen Radical Defense pathway and its epigenetic control Françoise van der Goot, Francisco Sarmento Mesquita, Laurence Abrami, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6339649/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Dec, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Membrane phospholipids are vulnerable to oxidative radicals, and uncontrolled lipid peroxidation affects cell viability. Cells have evolved quality control and defense mechanisms, of which the genetic regulation of is not fully understood. Here, we identify the Lipid Oxygen Radical Defense (LORD) pathway. It is epigenetically repressed, by a complex comprising the KRAB-zinc finger protein ZNF354A, the scaffold protein KAP1/TRIM28, the histone methyltransferase SETDB1, and the transcriptional activator ATF2. Upon lipid peroxide accumulation, p38- and JNK-dependent phosphorylation of ATF2, KAP1, and ZNF354A leads to disassembly of the repressive complex, releasing ZNF354A from specific DNA loci and activating a protective gene network, including NRF2 targets. The pathway thus controls cellular sensitivity to oxidative stress and ferroptosis, revealing a novel layer of epigenetic control in lipid quality control and damage defense. This positions the LORD pathway as a promising therapeutic target for diseases linked to chronic inflammation, neurodegeneration and cancer. Biological sciences/Cell biology/Cell signalling/Stress signalling Biological sciences/Chemical biology/Lipids ZNF354A ATF2 KAP1/TRIM28 KRAB-zinc finger protein Oxidative stress Lipid Peroxidation ferroptosis ZDHHC20 NRF2 Full Text Additional Declarations Yes there is potential Competing Interest. The authors declare that a patent application (EP25160082.1) related to the medical use of the findings reported in this study has been submitted. Supplementary Files FigS6.png Extended Data 6 FigS3.png Extended Data 3 FigS5.png Extended Data 5 FigS4.png Extended Data 4 FigS2.png Extended Data 2 FigS1.png Extended Data 1 20250305MesquitaetaldatasetRNAseqChIP293T.xlsx Supplementary Dataset 1 Cite Share Download PDF Status: Published Journal Publication published 11 Dec, 2025 Read the published version in Nature Communications → 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-6339649","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":449916883,"identity":"52681e9d-c79f-4b0b-a1b7-8bb777af410d","order_by":0,"name":"Françoise van der 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