A Two-Dimensional Peptide-Centric Stability Assay Maps Multidimensional Target Landscapes Unveiling 17β-Estradiol (E2)-GPX4 Binding-Induced Ferroptosis

A Two-Dimensional Peptide-Centric Stability Assay Maps Multidimensional Target Landscapes Unveiling 17β-Estradiol (E2)-GPX4 Binding-Induced Ferroptosis | 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 A Two-Dimensional Peptide-Centric Stability Assay Maps Multidimensional Target Landscapes Unveiling 17β-Estradiol (E2)-GPX4 Binding-Induced Ferroptosis Hailin Wang, Yanan Li, Di Yu, Haiyang Zhu, Sijie Mei, Kejia Li, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6893001/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 Current methods for mapping ligand-protein interactions struggle to resolve weak but critical binding events and conformational dynamics, particularly for endogenous hormones with pleiotropic functions like 17β-estradiol (E2). In this study, we developed a two-dimensional (2D) PEptide-centric Local Stability Assay (PELSA). By detecting increasing ligand dose-induced local binding rates in peptide-level, 2D-PELSA allows highly reliable target identification (~ 98% true identification for staurosporine) and systematic readout of ligand-induced multidimensional structural effects (direct interaction, allosteric regulation, complex regulation, etc.), as well as direct measurement of local binding affinities in native cellular environments. We then demonstrated the versatility of 2D-PELSA by investigating the interactions of 17β-estradiol (E2), a predominant sex hormone that exerts a wide spectrum function in both health and disease. As a result, 2D-PELSA totally detected 1134 conformotypic peptides, 112 E2-responsive segments, and 37 candidate targets with weak binding affinities (> μM), which were highly enriched in the process of fatty acid beta-oxidation. Among these proteins, GPX4, a key negative regulator of ferroptosis, was found to interact with E2 with an affinity of 2.0 μM and to be degraded upon E2 treatment at micromolar concentrations. This interaction was further validated by several Western- and MS-based orthogonal methods. Subsequent phenotype characterization and omics analysis indicated that chronic exposure to E2 in the micromolar range indeed facilitated oxidative, iron-dependent ferroptosis through shaping the cellular lipid composition. As an emerging analytical platform, 2D-PELSA is poised to become an important tool for structural biology and mechanism-driven applications in toxicology and drug discovery. Biological sciences/Chemical biology/Target identification Biological sciences/Biological techniques/Mass spectrometry Biological sciences/Biochemistry/Proteomics Biological sciences/Cell biology/Cell death Full Text Additional Declarations There is NO Competing Interest. Supplementary Table 13 is not available with this version. Supplementary Files SupplementaryTable1.xlsx Supplementary Table 1 SupplementaryTable2.xlsx Supplementary Table 2 SupplementaryTable3.xlsx Supplementary Table 3 SupplementaryTable4.xlsx Supplementary Table 4 SupplementaryTable5.xlsx Supplementary Table 5 SupplementaryTable6.xlsx Supplementary Table 6 SupplementaryTable7.xlsx Supplementary Table 7 SupplementaryTable8.xlsx Supplementary Table 8 SupplementaryTable9.xlsx Supplementary Table 9 SupplementaryTable10.xlsx Supplementary Table 10 SupplementaryTable11.xlsx Supplementary Table 11 SupplementaryTable12.xlsx Supplementary Table 12 SupplementaryTable14.xlsx Supplementary Table 14 SupplementaryFigures.pdf Supplementary Figures 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. 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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-6893001","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":475869842,"identity":"fdd61ebb-47e3-4ea2-b344-bf7605bd5108","order_by":0,"name":"Hailin 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In this study, we developed a two-dimensional (2D) PEptide-centric Local Stability Assay (PELSA). By detecting increasing ligand dose-induced local binding rates in peptide-level, 2D-PELSA allows highly reliable target identification (~ 98% true identification for staurosporine) and systematic readout of ligand-induced multidimensional structural effects (direct interaction, allosteric regulation, complex regulation, etc.), as well as direct measurement of local binding affinities in native cellular environments. We then demonstrated the versatility of 2D-PELSA by investigating the interactions of 17β-estradiol (E2), a predominant sex hormone that exerts a wide spectrum function in both health and disease. As a result, 2D-PELSA totally detected 1134 conformotypic peptides, 112 E2-responsive segments, and 37 candidate targets with weak binding affinities (\u003e μM), which were highly enriched in the process of fatty acid beta-oxidation. Among these proteins, GPX4, a key negative regulator of ferroptosis, was found to interact with E2 with an affinity of 2.0 μM and to be degraded upon E2 treatment at micromolar concentrations. This interaction was further validated by several Western- and MS-based orthogonal methods. Subsequent phenotype characterization and omics analysis indicated that chronic exposure to E2 in the micromolar range indeed facilitated oxidative, iron-dependent ferroptosis through shaping the cellular lipid composition. As an emerging analytical platform, 2D-PELSA is poised to become an important tool for structural biology and mechanism-driven applications in toxicology and drug discovery.","manuscriptTitle":"A Two-Dimensional Peptide-Centric Stability Assay Maps Multidimensional Target Landscapes Unveiling 17β-Estradiol (E2)-GPX4 Binding-Induced Ferroptosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-04 11:38:31","doi":"10.21203/rs.3.rs-6893001/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b89fce0d-a06c-49d3-b3e2-222151bdac9a","owner":[],"postedDate":"July 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":50531460,"name":"Biological sciences/Chemical biology/Target identification"},{"id":50531461,"name":"Biological sciences/Biological techniques/Mass spectrometry"},{"id":50531462,"name":"Biological sciences/Biochemistry/Proteomics"},{"id":50531463,"name":"Biological sciences/Cell biology/Cell death"}],"tags":[],"updatedAt":"2025-07-04T11:38:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-04 11:38:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6893001","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6893001","identity":"rs-6893001","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}