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While PRMT5 is known to regulate multiple oncogenic pathways, including PI3K-AKT signaling, its role in lipid metabolism and ferroptosis, a regulated, iron-dependent cell death driven by lipid peroxidation, remains poorly understood. Here, we identify a novel role for PRMT5 in suppressing ferroptosis in DLBCL and MCL cells through upregulation of SLC7A11, which imports cystine for glutathione (GSH) biosynthesis. This effect is mediated by the AKT-MYC-ATF5 signaling axis. ATF5, a MYC-regulated transcription factor overexpressed in these lymphomas, induces SLC7A11 expression. In addition, ATF5 promotes the expression of ATF4, another key regulator of the ferroptotic response, which forms heterodimers with ATF5 to further reinforce this regulatory network. PRMT5 inhibition sensitizes lymphoma cells to ferroptosis inducers such as dimethyl fumarate (DMF), an electrophile that irreversibly depletes GSH via succination. Notably, combined treatment with the PRMT5 inhibitor GSK3326595 and DMF synergistically enhances anti-tumor activity in a patient-derived xenograft (PDX) model. These findings reveal a previously unrecognized PRMT5-ATF5-SLC7A11 axis that drives ferroptosis resistance in B-cell lymphomas and provide a strong rationale for targeting PRMT5 to potentiate ferroptosis-based therapies in relapsed or refractory disease.<\/jats:p>","DOI":"10.1038\/s41375-026-02932-3","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:35:33Z","timestamp":1776404133000},"page":"1247-1260","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis"],"prefix":"10.1038","volume":"40","author":[{"given":"Yunxia","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3220-1955","authenticated-orcid":false,"given":"Qinyu","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyan","family":"Zai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria A.","family":"Obernberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavinu","family":"Weerawardhene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor K.","family":"Tourdot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Petta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison J.","family":"Conyers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2276-6731","authenticated-orcid":false,"given":"Christian M.","family":"Capitini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-8937","authenticated-orcid":false,"given":"Lixin","family":"Rui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2932_CR1","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1182\/blood.2022015851","volume":"140","author":"E Campo","year":"2022","unstructured":"Campo E, Jaffe ES, Cook JR, Quintanilla-Martinez L, Swerdlow SH, Anderson KC, et al. 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These companies had no input in the study design, analysis, manuscript preparation or decision to submit for publication. All other authors declare they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. Primary human MCL samples were obtained as de\u2011identified specimens with informed consent and under IRB\u2011approved protocols. Animal experiments in this study were approved by the Animal Care and Use Committee (IACUC) of the University of Wisconsin\u2013Madison (protocol M005915). De\u2011identified human samples were expanded in NSG mice before use.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}