Abstract
The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into S-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.
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Data availability
Uncropped images for immunoblots and statistics data are available as source data. All other relevant data are available in the article and Supplementary Tables as well as from the corresponding author upon reasonable request. Mass spectrometry data have been deposited in ProteomeXchange with the accession code PXD059133. The UniProt protein database (EMBL-EBI) was used for protein identification. Source data are provided with this paper.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (81925028 and 82230097 to L.L.) and the National Key Research and Development Program of China (2023YFC3404104 to L.L.) and Innovation Capacity Support Program of Shaanxi Province (2024ZC-KJXX-090 to Y.F.). We thanks X. Wei for synthesis of IKE, which was used in all animal experiments and partial cell experiments.
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L.L., B.G. and W.W. designed and supervised all experiments and contributed to manuscript preparation. Y.F., Y. Wang, W.D., L.N., Z.M., Yilei Zang, T.L., B.L., Y. Wei, Z.W., M.L., L.Y., Y.L., C.G., J.A., C.W., Yulin Zhang and J.Z. performed the experiments, analysed the data and contributed to manuscript preparation. Y. Zhuang, B.L. and L.Y. collected mouse samples and participated in the mouse experiments. L.N. collected zebrafish samples and participated in the zebrafish experiments. Z.W. created all graphic schematics with open-source elements. Y. Wang, Y.F. and J.Z. wrote the manuscript. B.G., W.W. and L.L. reviewed and edited the manuscript.
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W.W. is a co-founder and consultant for Rekindle Therapeutics. B.G. reports receiving consultation fees from Guidepoint Global, Cambridge Solution and NGM Bio, and is an inventor with patent applications involving targeting ferroptosis in cancer therapy. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Methionine deprivation promotes ferroptosis activation through SAM.
a, The top-ranked genes identified in RSL3-treated HEK-293T-Cas9 cells, top screen hits are shown in red (pro-ferroptotic), blue (anti-ferroptotic) and purple (MAT2A). The P value and fold change are generated by the MAGeCK-RRA algorithm. b-c, HEK-293T and HeLa cells stably expressing tet-on shScr or shMAT2A pretreated with doxycycline (Dox, 1 μg/mL) for 2 days. were treated with IKE or RSL3, cell viability (b) and lipid ROS was measured (c). d-e, HEK-293T and HeLa cells pretreated with FIDAS-5, were treated with Erastin, lipid ROS (d) and cell viability were measured (e). f-j, HeLa cells were deprived of methionine for 12 h, treated with Erastin, RSL3, and Fer-1. Lipid ROS-positive cells (f) and cellular MDA level (g) and cell viability (h, I, j) were measured. k, Dotplot showing correlation between prostate cancer cell sensitivity to IKE (IC50) and cellular SAM (left) or SAH (right) abundance. l-m, mRNA expression of GPX4 in HeLa cells deprived of methionine for 12 h and restimulated with SAM (100 μM), SAH (100 μM) for 4 h (l), or HeLa cells stably expressing tet-on shScr or tet-on shMAT2A (m). n, HKE-293T cells were transfected with Flag-vector or Flag-GPX4, cell lysates and the immunocomplexes from anti-Flag immunoprecipitants were analyzed by western blotting using indicated antibodies. o-p, HeLa cells were deprived of methionine for 12 h and restimulated with SAM (100 μM), SAH (100 μM) for 4 h, After treated with RSL3, Lipid ROS (o) and cell viability (p) were measured. q, Jurkat and THP-1 were deprived of methionine for indicated times (upper) or treated with indicated concentrations of FIDAS-5 for 24 h (lower), cell lysates were analyzed by immunoblotting with the indicated antibodies. r-y, Indicated cells were deprived of methionine for 12 hours or pretreated with FIDAS-5 (20 μM) for 24 h, then treated with Erastin and Fer-1, Lipid ROS levels and cell viability were measured. For b-j, o-p, r-y data are mean ± s.d. of n = 3 biological replicates, For l-m data are mean ± s.d. of n = 4 biological replicates. P values were calculated using a two-tailed Student’s t-test. All of the experiments, excluding CRISPR-based screen, were repeated at least twice independently, yielding identical outcomes. CM: complete medium.
Extended Data Fig. 2 Symmetric dimethylation of GPX4 at R152.
a, GPX4 immunoprecipitated from HEK-293T were separated by SDS–PAGE, and collected for mass spectrometry analysis. Mass spectrometry analysis shows the arginine methylation of R152 in GPX4. b-d, Titration of the indicated GPX4 peptides with or without R152 systematic dimethylation (b) demonstrates that the generated GPX4 R152-me2s antibodies specifically recognize the GPX4-R152-SDMe epitope in the dot blot analysis (c), and IB analysis of anti-Flag IPs derived from HEK-293T cells transfected with wild-type or R152K mutant Flag-GPX4 (d). e-f, Schematic representation of the genome sequence to generate GPX4-R152K CRISPR knock-in cells (e, upper). Identification of the potential knock-in mutants. Genomic DNA containing GPX4-R152K mutation was amplified by PCR and digested with BamHI (e, lower). Confirmation of the correct mutation of GPX4-R152K by Sanger DNA sequencing (f). g, IB analysis of the WCL derived from indicated HeLa after treated with MG132 (20 μM) for 12 h. h-j, IB analysis (h, left) of Parental and homozygous GPX4-R152K mutant HeLa cells, IB analysis (h, right), CHX chase assay (i), in vitro ubiquitination assay (j) of HeLa GPX4-knockout cells transfected with wild-type or the R152K mutant Flag-GPX4. Where indicated, MG132 (10 μM, 12 h) and CQ (50 nM, 24 h) were add in medium. All of the experiments, from c to j, were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 3 GPX4-R152 methylation promotes ferroptosis resistance in vitro.
a-c, Parental HeLa cells and the indicated clones with knock-in expression of GPX4-R152K mutant, were treated with or without cystine deprivation, Erastin (20 μM) and RSL3 (2 μM) for 6 h in the absence or presence of pretreated with Fer-1 (2 μM) for 2 h. Basal ROS levels (a), lipid ROS levels (b), and relative MDA levels (c) were measured. d-f, HeLa GPX4-knockout cells transfected with wild-type or the R152K mutant Flag-GPX4, were treated with or without cystine deprivation, Erastin (20 μM), and RSL3 (2 μM) for 6 h in the absence or presence of pretreated with Fer-1 (2 μM) for 2 h. Basal ROS levels (d), lipid ROS levels (e), and relative MDA levels (f) were measured. g-h, C4-2 GPX4-knockdown cells transfected with wild-type or the R152K mutant Flag-GPX4, were treated with or without cystine deprivation, Erastin (10 μM), and RSL3 (1 μM) for 6 h in the absence or presence of pretreated with Fer-1 (2 μM) for 2 h. Basal ROS levels (g) and lipid ROS levels (h) were measured. i-j, HeLa GPX4-knockout cells transfected with wild-type or the R152K mutant Flag-GPX4 (i), C4-2 GPX4-knockdown cells transfected with wild-type or the R152K mutant Flag-GPX4 (j), were treated with indicated concentrations of IKE and RSL3 for 24 h. Cell death were measured. k, Parental HeLa cells and the indicated clones with knock-in expression of GPX4-R152K mutant, were treated with or without Erastin (20 μM) and RSL3 (2 μM) for 24 h, then cultured for 2 weeks. Relative colony number were measured. l, HeLa GPX4-knockout cells transfected with wild-type or the R152K mutant Flag-GPX4, were treated with or without Erastin (20 μM) and RSL3 (2 μM) for 24 h, then cultured for 2 weeks. Relative colony number were measured. For a-l, data are mean ± s.d. of n = 3 biological replicates, P values were calculated using a two-tailed Student’s t-test. All of the experiments were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 4 GPX4-R152 methylation promotes ferroptosis resistance in vivo.
a, Representative image and statistical analysis of IHC staining of indicated antibodies from xenograft tumors from Fig. 2k. b-f, Wild-type or R152 mutant Flag-GPX4 were transinfected into GPX4-knockout HeLa cells, then cells were subjected to mouse xenograft assays. When the tumor reached 50 mm3, the mice were assigned randomly into different treatment groups treat with IKE (100 mg/kg, intraperitoneal, daily). Tumor sizes were monitored (b), and dissected tumors were weighed (c-d), Representative image (e) and statistical analysis (f) of IHC staining of indicated antibodies from xenograft tumors from c. n = 5 mice. Scale bar, 100 μm. Data are the mean ± s.d. g-k, Wild-type or R152 mutant Flag-GPX4 were transinfected into GPX4-knockdown C4-2 cells, then cells were subjected to mouse xenograft assays. When the tumor reached 50 mm3, the mice were assigned randomly into different treatment groups treat with IKE (100 mg/kg, intraperitoneal, daily). Tumor sizes were monitored (g), and dissected tumors were weighed (h-i). Representative image (j) and statistical analysis (k) of IHC staining of indicated antibodies from xenograft tumors from h. n = 5 mice. Scale bar, 100 μm. Data are the mean ± s.d. For b and g, P values were calculated using a log-rank test (two-tailed). For a, c-d, f, i and k, data are mean ± s.d. of n = 5 biological replicates, P values were calculated using a two-tailed Student’s t-test.
Extended Data Fig. 5 PRMT5 is the arginine methyltransferase of GPX4.
a, c IB analysis of the HA immunoprecipitant and WCL derived from HEK-293T cells that ectopically express HA-GPX4 (mitochondrial) and indicated GFP-PRMTs constructs. b, Upper: IB analysis of WCL and the immunocomplexes from anti-HA IPs and derived from HEK-293T cells that ectopically express HA-GPX4 (mitochondrial) and wild-type or catalytically dead (E444Q) GFP-PRMT5. Lower: Sequence alignment of partial human mitochondrial and cytoplasmic GPX4. d, C4-2 cells stably expressing shPRMT5 was transinfected with Flag-empty vector (EV), wild-type or E444Q mutant Flag-PRMT5. WCLs were analyzed by immunoblotting with the indicated antibodies. e, qRT–PCR analysis of the mRNA expression of the indicated genes of 786-O and C4-2 cells stably expressing shScr or shPRMT5. f, 786-O, C4-2, and HeLa cells stably expressing shScramble or shPRMT5 were treated with MG132 (20 μM) or CQ (50 μM) for 12 h, WCLs were analyzed by immunoblotting with the indicated antibodies. g-h, The scores of GPX4 and R152-methylated GPX4 immunohistochemical (IHC) staining in 60 prostate (g) and 140 bladder cancer (h) sections and paired adjacent non-cancer tissues. Characteristics of boxplot in g (minimum, maximum and median): GPX4 in adjacent tissue (0, 6, 1), GPX4 in cancer tissue (1, 9, 4). GPX4 R152-me2s in adjacent tissue (0, 4, 2), GPX4 R152-me2s in cancer tissue: minimum (0, 8, 3). Characteristics of boxplot in h (minimum, maximum and median): GPX4 in adjacent tissue (0, 9, 4), GPX4 in cancer tissue (0, 12, 6). GPX4 R152-me2s in adjacent tissue (1, 8, 4), GPX4 R152-me2s in cancer tissue: minimum (0, 12, 6). The horizontal lines mark the median, and the box limits indicate the 25th and 75th percentiles. i, k, m, Representative images of PRMT5, GPX4, and R152-methylated GPX4 staining were shown in lung cancer sections (i), renal cell cancer sections (k), and bladder cancer sections (m).Scale bar, 100 μm. j, l, n, The correlations between PRMT5 and GPX4 levels, PRMT5 and R152-methylated GPX4 levels in 150 consecutive lung tumor sections (j), 90 consecutive kidney tumor sections (l) and 140 consecutive bladder tumor sections (n) that were semiquantified as high or low and analyzed by Spearman rank correlation test. For e, data are mean ± s.d., For e, g, h, data, P values were calculated using a two-tailed Student’s t-test. All of the experiments, from a to f, were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 6 PRMT5 methylates GPX4 to induce ferroptosis resistance in vitro.
a, e, g, h Depletion of PRMT5 in human tumor cells and parental tumor cells were treated with cystine deprivation, Erastin, RSL3 or Fer-1. Lipid ROS levels (a), cell viability (e), and colony number (g, h) were measured. b-d, f, i, j Human tumor cells were pretreated with or without GSK3326595 (20 μM) combined with cystine deprivation, Erastin, RSL3 or Fer-1. Lipid ROS levels (b), MDA level (c, d), cell viability (f), and colony number (i, j) were measured. k, Depletion of PRMT5 in human tumor cells and parental tumor cells were treated with or without Erastin or cystine deprivation. Reduced GSH levels were measured. l-m, qRT–PCR analysis of the mRNA expression of the indicated genes of HeLa and C4-2 after PRMT5 or GSTA1 knockdown. n, Depletion of indicated genes in human tumor cells HeLa and C4-2 were treated with cystine deprivation for 6 h. Reduced GSH levels were measured. o, Zebrafish embryos with prmt5 knockdown by Morpholino Anti-sense oligos (MO) was analyzed by IB via indicated antibodies. p, Jurkat and THP-1 were treated with indicated concentrations of GSK3326595 for 24 h, cell lysates were analyzed by immunoblotting with the indicated antibodies. q-u, Indicated cells were pretreated with GSK3326595 (30 μM) for 24 h, then treated with Erastin, RSL3, IKE, and Fer-1, Lipid ROS levels and cell viability was measured. For a-o, q-u, data are mean ± s.d. of n = 3 biological replicates, P values were calculated using a two-tailed Student’s t-test. All of the experiments were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 7 Cullin1-FBW7 mediates GPX4 ubiquitin-proteasome degradation.
a, HEK-293T and HeLa cells were treated with indicated concentration of MG132 or MLN4924, Cell lysates were analyzed by western blotting using anti-GPX4 antibodies. b, Cell lysates from HeLa cells infected with the indicated shRNA lentiviruses were analyzed by western blotting using anti-GPX4 antibody. c-d, C4-2 cells were transfected with Flag-GPX4 and different mass of Myc-Cullin1, Cell lysates were analyzed by western blotting using anti-GPX4 antibodies. e, j qRT–PCR analysis of the mRNA expression of the indicated genes in C4-2 cells with Cullin1 (e) or FBW7 (e) knockdown. f, shScr and shCullin1 C4-2 cells were treated with 200 μg/mL CHX. At the indicated time points, Cell lysates were analyzed by western blotting using anti-GPX4 antibody. g, h, i indicated C4-2 cells were transfected with Flag-GPX4, His-Ub or Myc-Cullin1. 36 h after transfection, cells were treated with MG132(10 μM) for 6 h before cell collection. Cell lysates and the immunocomplexes from His-tag pulldown were analyzed by western blotting using indicated antibodies. k, C4-2 cells stably expressing shScr or shFBW7 were treated with MG132 (20 μM) or CQ (50 μM) for 12 h, cell lysates were analyzed by immunoblotting with the indicated antibodies. l, shScr and shFBW7 C4-2 cells were transfected with Flag-GPX4 and His-Ub. 36 h after transfection, cells were treated with MG132 (10 μM) for 6 h before cell collection. Cell lysates and the immunocomplexes from Ni-NTA pulldown were analyzed by western blotting using indicated antibody. m-n, shScr and shFBW7 HEK-293T cells were transfected with indicated FBW7 constructs, Cell lysates and were analyzed by western blotting using indicated antibodies. o-q, shScr and shFBW7 HEK-293T cells were transfected with Flag-GPX4 together with indicated FBW7 constructs and indicated His-Ub constructs. 36 h after transfection, cells were treated with MG132 (10 μM) for 6 h before cell collection. Cell lysates and the immunocomplexes from His-tag pulldown were analyzed by western blotting using indicated antibody. Ni-NTA: nickel-nitrilotriacetic acid, Ub: ubiquitin. For e and j, data are mean ± s.d. of n = 3 biological replicates, P values were calculated using a two-tailed Student’s t-test. All of the experiments were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 8 GPX4 T40/S44 phosphorylation prerequisites GPX4 for binding with FBW7.
a, HEK-293T cells were transfected with indicated Flag-GPX4 constructs, Cell lysates and the immunocomplexes from anti-Flag immunoprecipitant were analyzed by western blotting using indicated antibodies. b, HEK-293T cells were transfected with HA-FBW7 together indicated Flag-GPX4 constructs, Cell lysates and the immunocomplexes from anti-HA immunoprecipitant were analyzed by western blotting using indicated antibodies. c, HEK-293T cells were transfected with HA-FBW7 together with indicated Flag-GPX4 constructs or His-Ub, Cell lysates and the immunocomplexes from Ni-NTA pulldown were analyzed by western blotting using indicated antibodies. d-g, HEK-293T cells were transfected with indicated Flag-GPX4, HA-FBW7, and Myc-Cullin1 constructs. Cell lysates were analyzed by western blotting using indicated antibodies. h, HEK-293T cells were transfected with HA-FBW7 together with Flag-GPX4 constructs followed by indicated kinase inhibitor treatment, Cell lysates and the immunocomplexes from anti-HA immunoprecipitant were analyzed by western blotting using indicated antibodies. i-m, shGPX4 C4-2 cells stably expressing wild-type, T40E/S44E (EE) or T40A/S44A (AA) GPX4 were subjected to mouse xenograft assays. When the tumor reached 50 mm3, the mice were assigned randomly into different treatment groups treat with or without IKE (100 mg/kg). Tumor sizes were monitored (i), and dissected tumors were weighed (j-k), Reprehensive image (l) and statistical analysis (m) of IHC staining with indicated antibodies of xenograft tumors from j were shown. Scale bar, 100 μm. Data in i, k and m represent the mean ± s.e.m., n = 5 mice. For i, P values were calculated using a two-tailed log-rank test. For k and m, P values were calculated using a two-tailed Student’s t-test. All of the experiments, from a to h, were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 9 PRMT5 blocks FBW7-mediated GPX4 degradation.
a, HEK-293T cells were transfected with indicated Flag-GPX4 constructs and treated with MG132 before cell collection. Cell lysates and the immunocomplexes from anti-Flag immunoprecipitant were analyzed by western blotting using indicated antibodies. b, HEK-293T cells were transfected with indicated Flag-GPX4 constructs together with HA-FBW7 and His-Ub and treated with MG132 before cell collection. Cell lysates and the immunocomplexes from Ni-NTA pulldown were analyzed by western blotting using indicated antibodies. c-d, HEK-293T cells stably expressing shCullin1 or shFBW7 were transfected with indicated Flag-GPX4. Cell lysates were analyzed by western blotting using indicated antibodies. e-f, HEK-293T cells were transfected with indicated Flag-GPX4 constructs, then treated with 100 μg/mL cycloheximide (CHX). At the indicated time points, Cell lysates were analyzed by western blotting using anti-Flag antibodies. g, The structure of GPX4 exhibiting FBW7 phospho-degron sequences-T40/S44 and R152. h-k, Indicated HEK-293T cells transfected with indicated Flag-GPX4 together with HA-FBW7 and GPF-PRMT5 plasmids. Cell lysates and the immunocomplexes from anti-Flag or anti-HA immunoprecipitant were analyzed by western blotting using indicated antibodies. l, shPRMT5 HEK-293T cells were transfected with indicated HA-FBW7 and GFP-PRMT5 constructs. Cell lysates were analyzed by western blotting using indicated antibodies. m, n Indicated 786-O and C4-2 cells were treated with indicated concentrations of GSK3326595 for 24 h, cell lysates were analyzed by western blotting using indicated antibodies. o, HEK-293T cells were transfected with Flag-GPX4 together with HA-FBW7 and were treated with GSK3326595 before cell collection. Cell lysates and the immunocomplexes from anti-Flag immunoprecipitant were analyzed by western blotting using indicated antibodies. p, HEK-293T cells were transfected with Flag-GPX4 constructs together with HA-FBW7 and His-Ub and were treated with GSK3326595 and MG132 before cell collection. Cell lysates and the immunocomplexes from Ni-NTA pulldown were analyzed by western blotting using indicated antibodies. q, shScr and shFBW7 C4-2 cells were pretreated with GSK3326595, then treated with 200 μg/mL CHX at the indicated time points, Cell lysates were analyzed by western blotting using anti-GPX4 antibody. r-s, HEK-293T cells stably expressing shFBW7 were transfected with indicated Flag-GPX4 then were treated with GSK3326595 (10 μM) for 24 h. Cell lysates were analyzed by western blotting using indicated antibody. All of the experiments were repeated at least twice independently, yielding identical outcomes.
Extended Data Fig. 10 PRMT5 inhibitor sensitives cell to ferroptosis in vitro and in vivo.
a, Parental and PRMT5-deficient human tumor cells were treated with IKE and Fer-1. Lipid ROS levels were measured. b-d, Human tumor cells were pretreated with GSK3326595 followed by IKE and Fer-1 treatment. Lipid ROS (b), MDA (c) levels and cell viability (d) were measured. e, Depletion of FBW7 in human tumor cells and parental tumor cells were pretreated with GSK3326595 followed by treated with IKE or RSL3. Cell viability was measured. f-g, IB analysis and of cell lysates derived from MB49 (f) or C4-2 (g) implanted tumors in mice treated with GSK3326595 for 14 days. n = 5 mice per experimental group. h-l, C4-2 cells were subjected to mouse xenograft assays, When the tumor reached 50 mm3, the mice were assigned randomly into different treatment groups treat with RSL3 (100 mg/kg) combined with or without GSK3326595 (40 mg/kg), Tumor sizes were monitored (h) until the endpoint at day 30, and dissected tumors were weighed (i-j). Representative image (k) and statistical analysis (l) of IHC staining with the indicated antibodies of xenograft tumors from l. Scale bar, 100 μm. For a-e, data are mean ± s.d. of n = 3 biological replicates, P values were calculated using a two-tailed Student’s t-test. Data in f, h, j, l represent the mean ± s.e.m., n = 5 mice, P values were calculated using a two-tailed Student’s t-test. For k, P values were calculated using a log-rank test (two-tailed). m, By CRISPR–Cas9 screen of ferroptosis regulators, we identify MAT2A-induced GPX4 methylation as a new mechanism for ferroptosis resistance in cancer. In highly PRMT5-expressing cancers, GPX4 is methylated at R152 by PRMT5 to antagonize E3 ligase FBW7-regulated degradation, thereby promoting ferroptosis resistance. Targeting PRMT5 by GSK3326595 hinder GPX4 methylation, meanwhile, enhance GPX4 ubiquitination by Cullin1-FBW7 increasing cancer vulnerability during ferroptosis activation. All of the experiments, from a to e, were repeated at least twice independently, yielding identical outcomes.
Supplementary information
Supplementary Information
Supplementary Fig. 1.
Supplementary Tables
Supplementary Table 1. List of shRNA targets and primers. Related to Methods. Supplementary Table 2. Results of CRISPR-based screen with IKE. Supplementary Table 3. Results of CRISPR-based screen with RSL3.
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Source Data Tables 1–16
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Fan, Y., Wang, Y., Dan, W. et al. PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer. Nat Cell Biol 27, 641–653 (2025). https://doi.org/10.1038/s41556-025-01610-3
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DOI: https://doi.org/10.1038/s41556-025-01610-3
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