PRDX4 Activates the Dual Enzymatic Functions of IRE1α to Promote Ovarian Cancer Progression

PRDX4 Activates the Dual Enzymatic Functions of IRE1α to Promote Ovarian Cancer Progression | 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 PRDX4 Activates the Dual Enzymatic Functions of IRE1α to Promote Ovarian Cancer Progression Yingzhen Liu, Lisha Wu, Minghui Qiu, Jiashan Ding, Yufei Shen, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8481900/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Ovarian cancer is recognized as the most lethal gynecological malignancy, with high-grade serous carcinoma (HGSC) being the most prevalent and aggressive subtype. Due to the absence of typical early symptoms, the majority of patients are diagnosed at advanced stages, and effective biomarkers for early detection and prognosis remain elusive. Peroxiredoxin 4 (PRDX4), a cysteine-dependent peroxidase uniquely localized to the endoplasmic reticulum, has been implicated in protein folding and cellular homeostasis. However, its role in the progression of ovarian cancer has not been systematically investigated. This study aims to elucidate the expression patterns, biological functions, and molecular mechanisms of PRDX4 in HGSC. Methods: Transcriptomic and proteomic data from TCGA, GTEx, CPTAC, and an independent HGSC cohort were integrated to analyze PRDX4 expression and its clinical correlations. Immunohistochemistry was performed on patient tissues to validate PRDX4 expression. Functional assays, including proliferation, colony formation, apoptosis, migration, invasion, and xenograft tumor growth, were conducted in PRDX4 overexpression and knockdown cell models. Correlation analyses and molecular experiments were utilized to investigate the interaction between PRDX4 and the IRE1α pathway, with pharmacological inhibition applied to confirm functional relevance. Results Multi-omics analyses revealed that PRDX4 is significantly upregulated in ovarian cancer tissues, correlating with an increased likelihood of receiving hyperthermic intraperitoneal chemotherapy (HIPEC) and poorer overall survival outcomes. Immunohistochemistry further validated the overexpression of PRDX4 in HGSC specimens, which was associated with advanced FIGO stage. Functional assays demonstrated that PRDX4 promotes proliferation, migration, invasion, and tumor growth, whereas its knockdown suppressed these malignant phenotypes and induced apoptosis. Mechanistically, PRDX4 activates both enzymatic functions of IRE1α, facilitating XBP1s splicing and JNK–c-JUN signaling pathways. Pharmacological inhibition of IRE1α using Kira6 effectively abrogated PRDX4-driven proliferation and survival, confirming the reliance of PRDX4-mediated tumor progression on IRE1α activity. Conclusions PRDX4 is markedly overexpressed in ovarian cancer and is linked to adverse clinicopathological features and poor prognosis. By activating the dual functions of IRE1α, PRDX4 enhances tumor cell survival and invasiveness, highlighting its potential as a biomarker and therapeutic target in ovarian cancer. PRDX4 Ovarian cancer IRE1α pathway Tumor progression Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1.docx SupplementaryInformationfileOriginaldata0114.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 02 Apr, 2026 Editor assigned by journal 11 Feb, 2026 Submission checks completed at journal 11 Feb, 2026 First submitted to journal 06 Feb, 2026 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-8481900","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":616818362,"identity":"2d0ba767-806a-48ec-8afb-4375e1bf2a34","order_by":0,"name":"Yingzhen Liu","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Yingzhen","middleName":"","lastName":"Liu","suffix":""},{"id":616818363,"identity":"e09226c4-59b6-4cc2-890f-0c64fdbf407e","order_by":1,"name":"Lisha Wu","email":"","orcid":"","institution":"Institute of Medical Sciences, Xiangya Hospital, Central South University","correspondingAuthor":false,"prefix":"","firstName":"Lisha","middleName":"","lastName":"Wu","suffix":""},{"id":616818365,"identity":"0ed8ed80-8d9e-47b5-a91d-969b6907be6e","order_by":2,"name":"Minghui Qiu","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Minghui","middleName":"","lastName":"Qiu","suffix":""},{"id":616818368,"identity":"fac33963-4188-4bac-ad72-a004fe31fb9c","order_by":3,"name":"Jiashan Ding","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Jiashan","middleName":"","lastName":"Ding","suffix":""},{"id":616818370,"identity":"9ef6cb08-05ec-4946-9b8e-a2aa16758d4e","order_by":4,"name":"Yufei Shen","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Yufei","middleName":"","lastName":"Shen","suffix":""},{"id":616818372,"identity":"08931d3d-0e42-4f30-8bd4-b1f4b1a2a4f9","order_by":5,"name":"Shuran Tan","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Shuran","middleName":"","lastName":"Tan","suffix":""},{"id":616818374,"identity":"3e208eae-2cb1-4191-b2e1-b92358b6a54d","order_by":6,"name":"Yan Tian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBACPmbmhgOMDQw8DAzMBw58+EGEFjZmxoYDBxsMgFrYEg/O7CFGCwPQCqAWIJPH+DAHGzFa2BkbD3/c8UeGf3bPh8NA98nzix0gxmFnDHgk7pzdcLjAgsFw5uwEYrS0Af1yI3fD4Rk8DAkGt4nVIn8j58FhHjZStBjcyGEgQcvZNmMewxtpBsBAliDsF37+w4c/VLbJ2cvdSH784cMPG3l+aQJa0IEEacpHwSgYBaNgFGAHAMgKRu29FF0OAAAAAElFTkSuQmCC","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":true,"prefix":"","firstName":"Yan","middleName":"","lastName":"Tian","suffix":""},{"id":616818376,"identity":"9dd75c3c-211c-4cb9-b45c-129dfec7bf00","order_by":7,"name":"Yu Zhang","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-12-30 13:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8481900/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8481900/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106724187,"identity":"fdab4326-1c9f-4e4e-aa3a-84b8003bdc04","added_by":"auto","created_at":"2026-04-12 18:26:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1370951,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript0206.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8481900/v1_covered_aa618211-bccb-4196-82cf-afb34e9d0fcb.pdf"},{"id":106461072,"identity":"b213e536-e7b3-40c1-b966-17cbd5acf738","added_by":"auto","created_at":"2026-04-08 19:55:01","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":669006,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8481900/v1/cd22434886b70157e219f5ad.docx"},{"id":106461070,"identity":"69256690-e40e-4d05-860a-493b12235d86","added_by":"auto","created_at":"2026-04-08 19:55:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1672704,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformationfileOriginaldata0114.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8481900/v1/f3f5be2aed4a8d350ea51bd0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"PRDX4 Activates the Dual Enzymatic Functions of IRE1α to Promote Ovarian Cancer Progression","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":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"PRDX4, Ovarian cancer, IRE1α pathway, Tumor progression","lastPublishedDoi":"10.21203/rs.3.rs-8481900/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8481900/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOvarian cancer is recognized as the most lethal gynecological malignancy, with high-grade serous carcinoma (HGSC) being the most prevalent and aggressive subtype. Due to the absence of typical early symptoms, the majority of patients are diagnosed at advanced stages, and effective biomarkers for early detection and prognosis remain elusive. Peroxiredoxin 4 (PRDX4), a cysteine-dependent peroxidase uniquely localized to the endoplasmic reticulum, has been implicated in protein folding and cellular homeostasis. However, its role in the progression of ovarian cancer has not been systematically investigated. This study aims to elucidate the expression patterns, biological functions, and molecular mechanisms of PRDX4 in HGSC.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eTranscriptomic and proteomic data from TCGA, GTEx, CPTAC, and an independent HGSC cohort were integrated to analyze PRDX4 expression and its clinical correlations. Immunohistochemistry was performed on patient tissues to validate PRDX4 expression. Functional assays, including proliferation, colony formation, apoptosis, migration, invasion, and xenograft tumor growth, were conducted in PRDX4 overexpression and knockdown cell models. Correlation analyses and molecular experiments were utilized to investigate the interaction between PRDX4 and the IRE1α pathway, with pharmacological inhibition applied to confirm functional relevance.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMulti-omics analyses revealed that PRDX4 is significantly upregulated in ovarian cancer tissues, correlating with an increased likelihood of receiving hyperthermic intraperitoneal chemotherapy (HIPEC) and poorer overall survival outcomes. Immunohistochemistry further validated the overexpression of PRDX4 in HGSC specimens, which was associated with advanced FIGO stage. Functional assays demonstrated that PRDX4 promotes proliferation, migration, invasion, and tumor growth, whereas its knockdown suppressed these malignant phenotypes and induced apoptosis. Mechanistically, PRDX4 activates both enzymatic functions of IRE1α, facilitating XBP1s splicing and JNK\u0026ndash;c-JUN signaling pathways. Pharmacological inhibition of IRE1α using Kira6 effectively abrogated PRDX4-driven proliferation and survival, confirming the reliance of PRDX4-mediated tumor progression on IRE1α activity.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePRDX4 is markedly overexpressed in ovarian cancer and is linked to adverse clinicopathological features and poor prognosis. By activating the dual functions of IRE1α, PRDX4 enhances tumor cell survival and invasiveness, highlighting its potential as a biomarker and therapeutic target in ovarian cancer.\u003c/p\u003e","manuscriptTitle":"PRDX4 Activates the Dual Enzymatic Functions of IRE1α to Promote Ovarian Cancer Progression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-08 19:54:55","doi":"10.21203/rs.3.rs-8481900/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-02T19:54:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-11T19:06:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-11T10:28:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Ovarian Research","date":"2026-02-06T08:42:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d4989f8d-fb64-42a0-a248-738f109ef5cb","owner":[],"postedDate":"April 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T19:54:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-08 19:54:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8481900","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8481900","identity":"rs-8481900","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}