BCL6 Inhibition Sensitizes Diffuse Large B-cell Lymphoma Cells to Ferroptosis

BCL6 Inhibition Sensitizes Diffuse Large B-cell Lymphoma Cells to 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 BCL6 Inhibition Sensitizes Diffuse Large B-cell Lymphoma Cells to Ferroptosis Lei Xu, Yi Wen, Ran Zhong, Shun Zhang, Xuan Zhang, Jia Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9439017/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with a limited response to chemotherapy. Ferroptosis inducers have shown some efficacy in lymphoma treatment. However, there are some types of DLBCL cells that are resistant to ferroptosis through some unknown mechanism, which dramatically limits the application of this method. The transcriptional repressor BCL6 is a well-established oncogenic driver in a subset of DLBCL. We found that treatment with Imidazole Ketone Erastin (IKE), an inducer of ferroptosis, triggers a compensatory upregulation of BCL6. Pharmacological degradation or genetic knockdown of BCL6 synergistically sensitized DLBCL cells to IKE-induced ferroptosis in vitro and in vivo. Mechanism studies revealed that BCL6 knockdown aggravates mitochondrial damage, lipid peroxidation, and ROS accumulation in DLBCL. Proteomic analysis showed that the differentially expressed proteins after BCL6 knockdown were enriched in metabolic pathways, with SDHA and H6PD as core metabolic nodes, confirming that BCL6 mediates metabolic reprogramming in DLBCL cells. Public ChIP-seq data suggest that BCL6, together with SMRT and BCOR, may bind the ALOX5 promoter. In summary, the present study elucidates BCL6 as a critical adaptive resistor to ferroptosis and establishes the combined inhibition of SLC7A11 and BCL6 as a rational, synergistic strategy to overcome therapeutic resistance in DLBCL. Biological sciences/Cancer/Cancer therapy/Cancer therapeutic resistance Biological sciences/Cell biology/Cell death BCL6 Ferroptosis DLBCL IKE ALOX5 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Full Text Additional Declarations (Not answered) Supplementary Files SupplementaryTableS1.docx Supplementary Table S1 Originalfulllengthwesternblots.pdf Original full length western blots Cite Share Download PDF Status: Under Review Version 1 posted Reviewer # 1 agreed at journal 28 Apr, 2026 Reviewers invited by journal 28 Apr, 2026 Submission checks completed at journal 20 Apr, 2026 First submitted to journal 16 Apr, 2026 Editor assigned by journal 16 Apr, 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. 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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-9439017","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":630843657,"identity":"f83120dd-03d6-4b79-9d9f-60c1daab9bcc","order_by":0,"name":"Lei Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACNmbmAwYMBTYMbAwJBsRp4WdvSyhgMEgjQYtkzxmDDwwGh4FMYrUY3Egw3MxjcN6ejz15A8OPGgZ5cyK0JBvOMLjNzMbzrICx5xiD4c4GwlqOGXwwuM3GJpFjwMDbAHTeAYJaEtt/JBic4wFpYfxLjBbJnsMMQFsOSIC0MBNlCzCQGYB+STYA+eWwzDEJww2EtLAx838w5qmws5dvT9748E2NjTxBW1AAULEEKepHwSgYBaNgFOACANdhO4TAO/SZAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Institute of Materia Medica","correspondingAuthor":true,"prefix":"","firstName":"Lei","middleName":"","lastName":"Xu","suffix":""},{"id":630843658,"identity":"71e7b064-3fa0-4f90-b5b4-9355b0c8bef2","order_by":1,"name":"Yi Wen","email":"","orcid":"","institution":"Zhongshan City People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Wen","suffix":""},{"id":630843659,"identity":"ca730828-a662-4d2b-99be-7d96d6b1a737","order_by":2,"name":"Ran Zhong","email":"","orcid":"","institution":"Shanghai Institute of Materia Medica","correspondingAuthor":false,"prefix":"","firstName":"Ran","middleName":"","lastName":"Zhong","suffix":""},{"id":630843660,"identity":"a74216a1-4ad2-41cb-b4e9-dbdb88c91ead","order_by":3,"name":"Shun Zhang","email":"","orcid":"","institution":"Zhongshan City People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shun","middleName":"","lastName":"Zhang","suffix":""},{"id":630843661,"identity":"79ae0bef-6d21-4879-840a-0f5ffe9bb84c","order_by":4,"name":"Xuan Zhang","email":"","orcid":"","institution":"Shanghai Institute of Materia Medica","correspondingAuthor":false,"prefix":"","firstName":"Xuan","middleName":"","lastName":"Zhang","suffix":""},{"id":630843662,"identity":"f0057f9c-9b40-4c61-847c-91d4f63763e9","order_by":5,"name":"Jia Li","email":"","orcid":"https://orcid.org/0000-0003-3224-001X","institution":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-04-16 13:52:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9439017/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9439017/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108950062,"identity":"1d76bb1e-b222-4286-91ec-3d74a8d06f1e","added_by":"auto","created_at":"2026-05-11 07:02:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":402661,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 1. Targeting the SLC7A11/GPX4 axis inhibits DLBCL cell viability. (A, B) Expression of SLC7A11 (A) and GPX4 (B) in DLBCL patient tumor samples compared to normal B cells from the GSE56315 dataset. Data are presented as log₂-transformed expression values. ***P \u0026lt; 0.001, two-tailed Student's t-test. (C, D) DepMap CRISPR essentiality scores for SLC7A11 (C) and GPX4 (D) across 1 187 tumor cell lines (black) and 16 DLBCL cell lines (red). A more negative score indicates greater gene dependency. (E) Dose–response viability curves for a panel of DLBCL cell lines treated with IKE for 72 h. IC₅₀ values are indicated. Data are presented as mean ± SD (n = 3). (F) Dose–response viability curves of patient-derived DLBCL primary cells (PDCs) treated with IKE for 7 days. IC₅₀ values are indicated.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/8d6e5461473d6c39fb7e4247.png"},{"id":108978116,"identity":"f9492c1f-81ed-419a-bdcb-8ddfd205074e","added_by":"auto","created_at":"2026-05-11 11:34:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":334929,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2. IKE treatment upregulates BCL6 expression in a dose- and time-dependent manner. (A, B) BCL6 mRNA levels measured by RT-qPCR in SU-DHL-4 (A) and OCI-Ly10 (B) cells treated with the indicated concentrations of IKE or DMSO for 24 h. Data are presented as −ΔΔCt values relative to the DMSO control; n = 3. *P \u0026lt; 0.05, **P \u0026lt; 0.01, ***P \u0026lt; 0.001, one-way ANOVA. (C) BCL6 mRNA levels in OCI-Ly1 cells treated with the indicated concentrations of IKE for 24 h; n = 3. *P \u0026lt; 0.05, **P \u0026lt; 0.01, one-way ANOVA. (D) Western blot analysis of BCL6 protein expression in SU-DHL-4 cells treated with increasing concentrations of IKE for 72 h. α-Tubulin serves as the loading control. (E) Time-course Western blot analysis of BCL6 protein in SU-DHL-4 cells treated with 20 μM IKE for the indicated durations. Tubulin serves as the loading control.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/a52fdd805b089aaf4aef919e.png"},{"id":108950063,"identity":"715d991d-1d16-4612-9ca9-f44b900a8562","added_by":"auto","created_at":"2026-05-11 07:02:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3553869,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 3. BCL6 inhibition synergizes with IKE in DLBCL. (A) Synergy matrices and corresponding Bliss synergy landscapes for DLBCL cells (SU-DHL-4, OCI-Ly1, OCI-Ly10, Toledo, Pfeiffer) treated with the indicated concentrations of IKE and FX-1 for 7 days. (B) Synergy matrices and corresponding Bliss synergy landscapes for DLBCL cells (SU-DHL-4, OCI-Ly1, OCI-Ly10, U-2932) treated with the indicated concentrations of IKE and BI-3802 for 7 days. (C) Synergy matrix and Bliss synergy landscape for a patient-derived DLBCL primary cell culture (PDC, ZML-250072) treated with IKE and BI-3802 for 7 days. (D) BCL6 mRNA levels in SU-DHL-4NC and SU-DHL-4BCL6KD cells measured by RT-qPCR; n = 3. ***P \u0026lt; 0.001, two-tailed Student's t-test. (E) BCL6 protein expression confirmed by Western blot. α-Tubulin serves as the loading control. (F) Dose–response viability curves for SU-DHL-4NC and SU-DHL-4BCL6KD cells treated with IKE for 72 h: n = 3. Calculated IC₅₀ values are indicated.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/d4a2a073781a445f88b28a91.png"},{"id":108977574,"identity":"724a7309-7113-4b1b-8d94-eba05fe8adf9","added_by":"auto","created_at":"2026-05-11 11:32:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2113477,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 4. BCL6 deficiency potentiates IKE-induced ferroptosis. (A) Representative TEM images of SU-DHL-4NC and SU-DHL-4BCL6KD cells treated with DMSO or 20 μM IKE for 72 h. Arrowheads indicate shrunken mitochondria with condensed membranes and loss of cristae, characteristic ultrastructural features of ferroptosis. Scale bar: 2.0 μm. (B) Lipid peroxidation levels measured by flow cytometry using the Image-iT® Lipid Peroxidation Sensor in SUDHL- 4NC and SU-DHL-4BCL6KD cells treated with the indicated concentrations of IKE for 72 h. MFI, mean fluorescence intensity. (C) Intracellular ROS levels measured by flow cytometry using CM-H₂DCFDA in SU-DHL-4NC and SU-DHL-4BCL6KD cells treated with the indicated concentrations of IKE for 72 h. Data in (B) and (C) are presented as mean ± SD (n = 3); *P \u0026lt; 0.05, **P \u0026lt; 0.01, ***P \u0026lt; 0.001, ****P \u0026lt; 0.0001, two-way ANOVA.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/23da75f57754766f3193348b.png"},{"id":108950067,"identity":"41fd0f02-95a2-4601-a6db-161b21db6930","added_by":"auto","created_at":"2026-05-11 07:02:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2493944,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 5. Proteomic profiling identifies BCL6-regulated metabolic and redox pathways. (A) Venn diagrams showing overlap between DEPs in SU-DHL-4BCL6KD versus SU-DHL-4NC cells and curated databases of redox-related (left) and metabolism-related (right) proteins. (B) KEGG pathway enrichment analysis of the 214 redox-associated and 334 metabolismassociated overlapping DEPs from (A). Top 20 enriched pathways are shown. (C) Protein– protein interaction network of overlapping DEPs from (A), constructed using the STRING database. Node color (red intensity) and size correspond to betweenness centrality; hub proteins SDHA and H6PD are labeled. (D) Time-course Western blot analysis of SDHA protein expression in SU-DHL-4 cells treated with BI-3802 (5 μM) for the indicated number of days. α-Tubulin serves as the loading control.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/eed8c9fc3d794e8652730b80.png"},{"id":108950068,"identity":"e082defc-66f2-4b56-bd2b-f6ae7957dd12","added_by":"auto","created_at":"2026-05-11 07:02:08","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":266260,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 6. BCL6 transcriptionally represses the pro-ferroptotic gene ALOX5. (A) IGV snapshot of publicly available ChIP-seq tracks from Cistrome DB showing binding of BCL6 and its corepressors SMRT (NCOR2) and BCOR at the ALOX5 promoter region. (B) Western blot analysis of ALOX5 protein in SU-DHL-4 cells treated with BI-3802 (5 μM) for the indicated number of days. α-Tubulin serves as the loading control. (C) RT-qPCR analysis of BCL6 and ALOX5 mRNA levels in HEK293T cells transfected with a BCL6 overexpression plasmid or empty vector control; n = 3. Data are presented as mean ± SD; ***P \u0026lt; 0.001, twotailed Student's t-test. (D) Western blot confirming BCL6 overexpression and its suppressive effect on ALOX5 protein in HEK293T cells transfected as in (C).\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/3728d80fb5885b79f60ca9e6.png"},{"id":108950065,"identity":"f47d6b59-8c4f-4bca-a09b-483953ba4853","added_by":"auto","created_at":"2026-05-11 07:02:08","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1187932,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 7. Combined SLC7A11 and BCL6 inhibition suppresses DLBCL tumor growth in vivo. NOD/SCID mice bearing subcutaneous OCI-Ly10 xenograft tumors were randomized into five treatment groups (n = 6 per group): vehicle, IKE (25 mg/kg, i.p., daily), FX-1 (10 mg/kg, i.p., daily), IKE + FX-1, or ibrutinib (20 mg/kg, p.o., daily). (A) Schematic illustration of OCI-Ly10 subcutaneous xenograft model establishment and experimental design. (B) Body weight changes of OCI-Ly10 xenograft mice during treatment. (C) Relative tumor volume changes of OCI-Ly10 xenograft mice during treatment. (D) Excised OCI-Ly10 xenograft tumor weights at endpoint. Statistical comparisons were performed between the IKE, FX-1, IKE+FX-1, and ibrutinib groups versus the vehicle control group. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 by one-way ANOVA. (E) Representative images of excised OCI-Ly10 xenograft tumors at endpoint.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/ccda4107a6903972359c5b46.png"},{"id":108950066,"identity":"18f7fbf2-f599-4d65-9f59-fa52c3902f04","added_by":"auto","created_at":"2026-05-11 07:02:08","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":1121731,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 8. Mechanism model of BCL6 inhibition synergistically enhancing IKE. (A) Western blot analysis of BCL6, ALOX5, and SDHA protein levels in SU-DHL-4 cells treated with 20 μM IKE, 1 μM BI-3802, or their combination for 72 hours. Quantification of band intensities using ImageJ. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, ****p \u0026lt; 0.0001 by one-way ANOVA. (B) Schematic model illustrating the proposed mechanism.\u003c/p\u003e","description":"","filename":"Fig8.png","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/d325bc2ec0a85e1e102c95e3.png"},{"id":109067560,"identity":"3fa1c24f-c9d6-4628-94a1-70c7d24b26fc","added_by":"auto","created_at":"2026-05-12 09:56:08","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5947422,"visible":true,"origin":"","legend":"Article File","description":"","filename":"BCL6InhibitionSensitizesDiffuseLargeBcellLymphomaCellstoFerroptosis.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1_covered_290dda97-0346-4244-883f-eb5320509b42.pdf"},{"id":108978210,"identity":"fcb05dab-fb94-4a4a-9635-eaf85237fcae","added_by":"auto","created_at":"2026-05-11 11:34:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13417,"visible":true,"origin":"","legend":"Supplementary Table S1","description":"","filename":"SupplementaryTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/80a965688cceab08aa3e52bb.docx"},{"id":108977845,"identity":"ea5ce23a-352b-4528-8412-133cc7a634b6","added_by":"auto","created_at":"2026-05-11 11:33:11","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":688812,"visible":true,"origin":"","legend":"Original full length western blots","description":"","filename":"Originalfulllengthwesternblots.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9439017/v1/771720e11eaac5ed14163e8a.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"BCL6 Inhibition Sensitizes Diffuse Large B-cell Lymphoma Cells to Ferroptosis","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":"BCL6, Ferroptosis, DLBCL, IKE, ALOX5","lastPublishedDoi":"10.21203/rs.3.rs-9439017/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9439017/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDiffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with a limited response to chemotherapy. Ferroptosis inducers have shown some efficacy in lymphoma treatment. However, there are some types of DLBCL cells that are resistant to ferroptosis through some unknown mechanism, which dramatically limits the application of this method. The transcriptional repressor BCL6 is a well-established oncogenic driver in a subset of DLBCL. We found that treatment with Imidazole Ketone Erastin (IKE), an inducer of ferroptosis, triggers a compensatory upregulation of BCL6. Pharmacological degradation or genetic knockdown of BCL6 synergistically sensitized DLBCL cells to IKE-induced ferroptosis in vitro and in vivo. Mechanism studies revealed that BCL6 knockdown aggravates mitochondrial damage, lipid peroxidation, and ROS accumulation in DLBCL. Proteomic analysis showed that the differentially expressed proteins after BCL6 knockdown were enriched in metabolic pathways, with SDHA and H6PD as core metabolic nodes, confirming that BCL6 mediates metabolic reprogramming in DLBCL cells. Public ChIP-seq data suggest that BCL6, together with SMRT and BCOR, may bind the ALOX5 promoter. In summary, the present study elucidates BCL6 as a critical adaptive resistor to ferroptosis and establishes the combined inhibition of SLC7A11 and BCL6 as a rational, synergistic strategy to overcome therapeutic resistance in DLBCL.\u003c/p\u003e","manuscriptTitle":"BCL6 Inhibition Sensitizes Diffuse Large B-cell Lymphoma Cells to Ferroptosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 07:02:03","doi":"10.21203/rs.3.rs-9439017/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-28T09:35:55+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-04-28T07:27:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-20T15:42:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cell Death \u0026 Disease","date":"2026-04-16T13:46:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-16T13:46:29+00:00","index":"","fulltext":""}],"status":"published","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}}],"origin":"","ownerIdentity":"b01acaf6-9f87-4a50-89fc-5d4a0ced6071","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67144767,"name":"Biological sciences/Cancer/Cancer therapy/Cancer therapeutic resistance"},{"id":67144768,"name":"Biological sciences/Cell biology/Cell death"}],"tags":[],"updatedAt":"2026-05-11T07:02:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 07:02:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9439017","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9439017","identity":"rs-9439017","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}