PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis

Leukemia ARTICLE www.nature.com/leu OPEN PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis Yunxia Liu1,2, Ruoyu Chen1,2, Xiaoyue Gao1,2, Fen Zhu1,2, Qinyu Ni 1,2, Paul D. Bates2,3, Sunny Wu1,2, Zhuoyan Zai1,2, Victoria A. Obernberger1,2, Kavinu Weerawardhene1,2, Taylor K. Tourdot1,2, Sophie Petta1,2, Madison J. Conyers1,2, ✉ Christian M. Capitini 2,3 and Lixin Rui 1,2 1234567890();,: © The Author(s) 2026 Protein arginine methyltransferase 5 (PRMT5) is overexpressed in B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). 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. Leukemia; https://doi.org/10.1038/s41375-026-02932-3 INTRODUCTION Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies, comprising over two dozen diagnostic entities, each with distinct molecular and genetic profiles, as well as varying pathological courses and clinical features [1]. Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell NHL, accounting for 30-40% of lymphoma cases [1]. It has two main subtypes: germinal center B cell-like (GCB) and activated B cell-like (ABC) [2]. DLBCL has also been classified into up to seven distinct subgroups based on clustering of genetic alterations, enhancing the prediction of responses to first-line and targeted therapies [3, 4]. Despite advances in molecular classification, one-third of DLBCL patients relapse from or do not respond to first-line immunochemotherapy, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [5–7]. Salvage treatments such as second-line chemotherapies (e.g., DHAP, ICE), targeted therapies (e.g., BTK inhibitors, CAR T-cell therapy), or stem cell transplantation are effective in fewer than 30% to 50% of these relapsed/refractory patients [8–12]. Mantle cell lymphoma (MCL) is a rare type of B-cell NHL that makes up about 6% of cases and is currently considered incurable [13, 14]. A hallmark of MCL is the t(11;14)(q13;q32) translocation, which juxtaposes the cyclin D1 proto-oncogene (CCND1) with the immunoglobulin heavy chain gene (IgH) and results in the constitutive expression of CCND1 [14]. There is currently no universally accepted standard of care for MCL. In addition to immunochemotherapy such as R-CHOP, targeted therapeutic strategies have been widely employed in its management. These include single or combination therapies with BTK inhibitors (e.g., ibrutinib, zanubrutinib, acalabrutinib, pirtobrutinib) [15–18], the BCL2 inhibitor venetoclax [19, 20], and CAR T-cell therapy [21, 22]. Although response rates to these therapies are usually high, the vast majority of patients still do not achieve long-term survival. PRMT5, which regulates gene expression by symmetric dimethylation of histones and non-histone target proteins, is overexpressed and plays a pathogenic role in various solid tumors and hematological malignancies [23–27]. Our recent study has demonstrated that PRMT5 expression is upregulated in DLBCL and MCL [28]. PRMT5 overexpression promotes cell proliferation and survival in these lymphoma cells through multiple mechanisms, such as activating the PI3K-AKT pathway, MYC target genes and lipid metabolic reprogramming [28–30]. PRMT5 directly methylates all three members of the AKT family [31, 32], and MYC is a downstream target of AKT signaling [28]. Targeting PRMT5 with specific inhibitors has revealed anti-tumor effects in preclinical studies [27–29, 33]. However, a recent Phase 1 trial reported that the use of a PRMT5 inhibitor alone shows limited efficacy in solid tumors and NHL, including DLBCL and MCL [34]. Ferroptosis is an iron-dependent form of regulated cell death triggered by the accumulation of lipid peroxides on cellular membranes [35, 36]. Ferroptosis can be prevented by different cellular defense systems including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11 or xCT) [37] and ferroptosis suppressor protein 1 (FSP1 or AIFM2). GPX4 uses 1 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 2Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 3Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. ✉email: Received: 6 January 2026 Revised: 9 February 2026 Accepted: 10 March 2026 Y. Liu et al. 2 0 1 2 3 4 5 6 DMF_20μM Z-138 shPRMT5#2 shPRMT5#1 shCtrl shPRMT5#2 shPRMT5#1 Solv shCtrl Count shPRMT5#2 shPRMT5#1 shCtrl shPRMT5#2 shPRMT5#1 shCtrl DMF_10μM Count Z-138 Solv 0 1 2 3 4 5 shPRMT5#2 shPRMT5#1 shCtrl shPRMT5#2 shPRMT5#1 shCtrl 6 0 1 2 3 4 5 DMF_40μM MCL Z-138 Count A Solv 6 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 BODIPY C11 BODIPY C11 BODIPY C11 B GCB-DLBCL ABC DLBCL 1 2 3 4 5 Count Count shPRMT5#2 shPRMT5#1 DMF shCtrl shPRMT5#2 shPRMT5#1 Solv shCtrl 0 OCI-Ly7 RIVA TMD8 6 shPRMT5#2 shPRMT5#1 DMF shCtrl shPRMT5#2 shPRMT5#1 Solv shCtrl 0 10 10 10 10 10 10 10 1 2 3 4 10 10 10 10 10 BODIPY C11 5 0 6 5 6 4 5 6 0 1 2 3 4 5 6 10 10 10 10 10 10 10 10 10 10 10 10 10 10 BODIPY C11 BODIPY C11 GSK3326595 EPZ015666 DMF Solv GSK3326595 EPZ015666 Solv Solv GSK3326595 EPZ015666 DMF Solv GSK3326595 EPZ015666 Solv Solv Count GSK3326595 EPZ015666 DMF Solv GSK3326595 EPZ015666 Solv Solv Count HBL1 Count 3 4 GCB-DLBCL OCI-Ly7 TMD8 2 3 BODIPY C11 ABC DLBCL 1 2 10 10 10 10 10 10 10 10 10 BODIPY C11 C 0 1 shPRMT5#2 shPRMT5#1 DMF shCtrl shPRMT5#2 shPRMT5#1 Solv shCtrl 0 1 2 3 4 5 6 10 10 10 10 10 10 10 BODIPY C11 (...truncated)