{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T21:43:12Z","timestamp":1784583792972,"version":"3.55.0"},"reference-count":162,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T00:00:00Z","timestamp":1696636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"5th Beca Carmen Delgado\/Miguel P\u00e9rez-Mateo de AESPANC-ACANPAN","award":["25791\/001"],"award-info":[{"award-number":["25791\/001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell\u2019s antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC.<\/jats:p>","DOI":"10.3390\/ijms241914979","type":"journal-article","created":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T14:03:03Z","timestamp":1696687383000},"page":"14979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Iron-Dependent Cell Death: A New Treatment Approach against Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"24","author":[{"given":"Carlos","family":"Lopez-Blazquez","sequence":"first","affiliation":[{"name":"Translational Oncology Division, OncoHealth Institute, Health Research Institute\u2014Fundaci\u00f3n Jimen\u00e9z Diaz, Fundaci\u00f3n Jimen\u00e9z D\u00edaz University Hospital\/Universidad Aut\u00f3noma de Madrid (IIS-FJD\/UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Lacalle-Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Sanz-Criado","sequence":"additional","affiliation":[{"name":"Translational Oncology Division, OncoHealth Institute, Health Research Institute\u2014Fundaci\u00f3n Jimen\u00e9z Diaz, Fundaci\u00f3n Jimen\u00e9z D\u00edaz University Hospital\/Universidad Aut\u00f3noma de Madrid (IIS-FJD\/UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ochieng\u2019 Otieno","sequence":"additional","affiliation":[{"name":"Translational Oncology Division, OncoHealth Institute, Health Research Institute\u2014Fundaci\u00f3n Jimen\u00e9z Diaz, Fundaci\u00f3n Jimen\u00e9z D\u00edaz University Hospital\/Universidad Aut\u00f3noma de Madrid (IIS-FJD\/UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Garcia-Foncillas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9007-828X","authenticated-orcid":false,"given":"Javier","family":"Martinez-Useros","sequence":"additional","affiliation":[{"name":"Translational Oncology Division, OncoHealth Institute, Health Research Institute\u2014Fundaci\u00f3n Jimen\u00e9z Diaz, Fundaci\u00f3n Jimen\u00e9z D\u00edaz University Hospital\/Universidad Aut\u00f3noma de Madrid (IIS-FJD\/UAM), 28040 Madrid, Spain"},{"name":"Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer Statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.12659\/AJCR.917297","article-title":"Retrograde Pancreatic Duct Stent Migration into the Biliary Tract Presenting as a Rare Early Complication of Pancreaticoduodenectomy (Whipple Procedure)","volume":"20","author":"Helaly","year":"2019","journal-title":"Am. J. Case Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1053\/j.gastro.2020.02.068","article-title":"Global Burden of 5 Major Types of Gastrointestinal Cancer","volume":"159","author":"Arnold","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Huang, L., Jansen, L., Balavarca, Y., Babaei, M., van der Geest, L., Lemmens, V., Van Eycken, L., De Schutter, H., Johannesen, T.B., and Primic-\u017dakelj, M. (2018). Stratified Survival of Resected and Overall Pancreatic Cancer Patients in Europe and the USA in the Early Twenty-First Century: A Large, International Population-Based Study. BMC Med., 16.","DOI":"10.1186\/s12916-018-1120-9"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S1470-2045(19)30456-5","article-title":"Progress in Cancer Survival, Mortality, and Incidence in Seven High-Income Countries 1995-2014 (ICBP SURVMARK-2): A Population-Based Study","volume":"20","author":"Arnold","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1158\/2159-8290.CD-18-0275","article-title":"Real-Time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine","volume":"8","author":"Aguirre","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e173420","DOI":"10.1001\/jamaoncol.2017.3420","article-title":"Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma","volume":"4","author":"Qian","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1158\/1078-0432.CCR-20-0418","article-title":"Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection","volume":"26","author":"Park","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41575-019-0109-y","article-title":"Molecular Subtypes of Pancreatic Cancer","volume":"16","author":"Collisson","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_10","unstructured":"(2023, March 22). Guidelines Detail. Available online: https:\/\/www.nccn.org\/guidelines\/guidelines-detail."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1159\/000510343","article-title":"Neoadjuvant Chemotherapy in Pancreatic Cancer: An Appraisal of the Current High-Level Evidence","volume":"106","author":"Frey","year":"2021","journal-title":"Pharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"StatBite (2010). U.S. Pancreatic Cancer Rates. J. Natl. Cancer Inst., 102, 1822.","DOI":"10.1093\/jnci\/djq517"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pusceddu, S., Ghidini, M., Torchio, M., Corti, F., Tomasello, G., Niger, M., Prinzi, N., Nichetti, F., Coinu, A., and Di Bartolomeo, M. (2019). Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis. Cancers, 11.","DOI":"10.3390\/cancers11040484"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"LBA661","DOI":"10.1200\/JCO.2023.41.4_suppl.LBA661","article-title":"NAPOLI-3: A Randomized, Open-Label Phase 3 Study of Liposomal Irinotecan + 5-Fluorouracil\/Leucovorin + Oxaliplatin (NALIRIFOX) versus Nab-Paclitaxel + Gemcitabine in Treatment-Na\u00efve Patients with Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)","volume":"41","author":"Wainberg","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.ccr.2012.04.024","article-title":"Oncogenic Kras-Induced GM-CSF Production Promotes the Development of Pancreatic Neoplasia","volume":"21","author":"Lee","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16031","DOI":"10.1038\/ncomms16031","article-title":"Collagen-Derived Proline Promotes Pancreatic Ductal Adenocarcinoma Cell Survival under Nutrient Limited Conditions","volume":"8","author":"Olivares","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1073\/pnas.1421601112","article-title":"Cholesterol Uptake Disruption, in Association with Chemotherapy, Is a Promising Combined Metabolic Therapy for Pancreatic Adenocarcinoma","volume":"112","author":"Guillaumond","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1158\/1078-0432.CCR-13-1320","article-title":"A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma","volume":"19","author":"Beatty","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1126\/science.1198443","article-title":"CD40 Agonists Alter Tumor Stroma and Show Efficacy against Pancreatic Carcinoma in Mice and Humans","volume":"331","author":"Beatty","year":"2011","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1158\/1078-0432.CCR-21-1047","article-title":"Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer","volume":"27","author":"Byrne","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1097\/SLA.0b013e3181fd271c","article-title":"A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma. A Phase II Trial of Safety, Efficacy, and Immune Activation","volume":"253","author":"Lutz","year":"2011","journal-title":"Ann. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of Ferroptotic Cancer Cell Death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kausar, S., Wang, F., and Cui, H. (2018). The Role of Mitochondria in Reactive Oxygen Species Generation and Its Implications for Neurodegenerative Diseases. Cells, 7.","DOI":"10.3390\/cells7120274"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How Mitochondria Produce Reactive Oxygen Species","volume":"417","author":"Murphy","year":"2009","journal-title":"Biochem. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.cmet.2020.10.011","article-title":"The Metabolic Underpinnings of Ferroptosis","volume":"32","author":"Zheng","year":"2020","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1242\/jeb.132142","article-title":"A Radical Shift in Perspective: Mitochondria as Regulators of Reactive Oxygen Species","volume":"220","author":"Munro","year":"2017","journal-title":"J. Exp. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cmet.2022.01.007","article-title":"The Hallmarks of Cancer Metabolism: Still Emerging","volume":"34","author":"Pavlova","year":"2022","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Le, A. (2021). The Heterogeneity of Cancer Metabolism, Springer International Publishing. Advances in Experimental Medicine and Biology.","DOI":"10.1007\/978-3-030-65768-0_19"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Le, A. (2021). The Heterogeneity of Cancer Metabolism, Springer International Publishing. Advances in Experimental Medicine and Biology.","DOI":"10.1007\/978-3-030-65768-0_19"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s10549-022-06633-0","article-title":"Abundance of Reactive Oxygen Species (ROS) Is Associated with Tumor Aggressiveness, Immune Response, and Worse Survival in Breast Cancer","volume":"194","author":"Oshi","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e152","DOI":"10.1038\/cddis.2011.36","article-title":"Gemcitabine\/Cannabinoid Combination Triggers Autophagy in Pancreatic Cancer Cells through a ROS-Mediated Mechanism","volume":"2","author":"Donadelli","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9348","DOI":"10.1074\/jbc.M113.510495","article-title":"NADPH Oxidase-Generated Hydrogen Peroxide Induces DNA Damage in Mutant FLT3-Expressing Leukemia Cells*","volume":"290","author":"Stanicka","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1038\/s41467-018-03917-2","article-title":"Genome-Wide and High-Density CRISPR-Cas9 Screens Identify Point Mutations in PARP1 Causing PARP Inhibitor Resistance","volume":"9","author":"Pettitt","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sun, Y., Qiao, Y., Liu, Y., Zhou, J., Wang, X., Zheng, H., Xu, Z., Zhang, J., Zhou, Y., and Qian, L. (2021). Ent-Kaurane Diterpenoids Induce Apoptosis and Ferroptosis through Targeting Redox Resetting to Overcome Cisplatin Resistance. Redox Biol., 43.","DOI":"10.1016\/j.redox.2021.101977"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e139434","DOI":"10.1172\/JCI139434","article-title":"TYRO3 Induces Anti\u2013PD-1\/PD-L1 Therapy Resistance by Limiting Innate Immunity and Tumoral Ferroptosis","volume":"131","author":"Jiang","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/cac2.12250","article-title":"Ferroptosis in Cancer and Cancer Immunotherapy","volume":"42","author":"Zhao","year":"2022","journal-title":"Cancer Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.bbamcr.2014.12.016","article-title":"Onconase Induces Autophagy Sensitizing Pancreatic Cancer Cells to Gemcitabine and Activates Akt\/mTOR Pathway in a ROS-Dependent Manner","volume":"1853","author":"Fiorini","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kong, R., Jia, G., Cheng, Z., Wang, Y., Mu, M., Wang, S., Pan, S., Gao, Y., Jiang, H., and Dong, D. (2012). Dihydroartemisinin Enhances Apo2L\/TRAIL-Mediated Apoptosis in Pancreatic Cancer Cells via ROS-Mediated up-Regulation of Death Receptor 5. PLoS ONE, 7.","DOI":"10.1371\/annotation\/f7203563-87dc-4d11-a1b7-958f81cf743a"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.4252\/wjsc.v12.i11.1410","article-title":"Glutathione Metabolism Is Essential for Self-Renewal and Chemoresistance of Pancreatic Cancer Stem Cells","volume":"12","author":"Jagust","year":"2020","journal-title":"World J. Stem Cells"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1096\/fj.09-149997","article-title":"Depletion of GSH in Glial Cells Induces Neurotoxicity: Relevance to Aging and Degenerative Neurological Diseases","volume":"24","author":"Lee","year":"2010","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/174689a0","article-title":"Free Radicals in Biological Materials","volume":"174","author":"Commoner","year":"1954","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nchembio.607","article-title":"Chemistry and Biology of Reactive Oxygen Species in Signaling or Stress Responses","volume":"7","author":"Dickinson","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1042\/bj3530411","article-title":"Mitochondrial Respiratory Chain-Dependent Generation of Superoxide Anion and Its Release into the Intermembrane Space","volume":"353","author":"Han","year":"2001","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1016\/j.freeradbiomed.2012.08.015","article-title":"Native Rates of Superoxide Production from Multiple Sites in Isolated Mitochondria Measured Using Endogenous Reporters","volume":"53","author":"Quinlan","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2105053118","DOI":"10.1073\/pnas.2105053118","article-title":"Cytoglobin Has Potent Superoxide Dismutase Function","volume":"118","author":"Zweier","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101203","DOI":"10.1016\/j.molmet.2021.101203","article-title":"Loss of Mitochondrial Aconitase Promotes Colorectal Cancer Progression via SCD1-Mediated Lipid Remodeling","volume":"48","author":"You","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1039\/CT8946500899","article-title":"LXXIII.\u2014Oxidation of Tartaric Acid in Presence of Iron","volume":"65","author":"Fenton","year":"1894","journal-title":"J. Chem. Soc. Trans."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.4049\/jimmunol.1201725","article-title":"Activation of TLR4 Is Required for the Synergistic Induction of Dual Oxidase 2 and Dual Oxidase A2 by IFN-\u03b3 and Lipopolysaccharide in Human Pancreatic Cancer Cell Lines","volume":"190","author":"Wu","year":"2013","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3699","DOI":"10.1038\/sj.onc.1209406","article-title":"Inhibition of NADPH Oxidase 4 Activates Apoptosis via the AKT\/Apoptosis Signal-Regulating Kinase 1 Pathway in Pancreatic Cancer PANC-1 Cells","volume":"25","author":"Mochizuki","year":"2006","journal-title":"Oncogene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1053\/j.gastro.2007.08.022","article-title":"NADPH Oxidase Promotes Pancreatic Cancer Cell Survival via Inhibiting JAK2 Dephosphorylation by Tyrosine Phosphatases","volume":"133","author":"Lee","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1042\/BST20140060","article-title":"ROS Signalling, NADPH Oxidases and Cancer","volume":"42","author":"Landry","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.semcdb.2017.05.023","article-title":"ROS Signalling in the Biology of Cancer","volume":"80","author":"Moloney","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nrd4002","article-title":"Modulation of Oxidative Stress as an Anticancer Strategy","volume":"12","author":"Gorrini","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1161\/CIRCULATIONAHA.109.900928","article-title":"Reduction of AMP-Activated Protein Kinase Alpha2 Increases Endoplasmic Reticulum Stress and Atherosclerosis in Vivo","volume":"121","author":"Dong","year":"2010","journal-title":"Circulation"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ma, W.F., Boudreau, H.E., and Leto, T.L. (2021). Pan-Cancer Analysis Shows TP53 Mutations Modulate the Association of NOX4 with Genetic Programs of Cancer Progression and Clinical Outcome. Antioxidants, 10.","DOI":"10.3390\/antiox10020235"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"33586","DOI":"10.18632\/oncotarget.16829","article-title":"Overexpression of NOX4 Predicts Poor Prognosis and Promotes Tumor Progression in Human Colorectal Cancer","volume":"8","author":"Lin","year":"2017","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.4049\/jimmunol.173.6.3589","article-title":"Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-Kappa B","volume":"173","author":"Park","year":"2004","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e2104384","DOI":"10.1002\/advs.202104384","article-title":"Photoinactivation of Catalase Sensitizes Candida Albicans and Candida Auris to ROS-Producing Agents and Immune Cells","volume":"9","author":"Dong","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Calvani, N.E.D., De Marco Verissimo, C., Jewhurst, H.L., Cwiklinski, K., Flaus, A., and Dalton, J.P. (2022). Two Distinct Superoxidase Dismutases (SOD) Secreted by the Helminth Parasite Fasciola Hepatica Play Roles in Defence against Metabolic and Host Immune Cell-Derived Reactive Oxygen Species (ROS) during Growth and Development. Antioxidants, 11.","DOI":"10.3390\/antiox11101968"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1089\/152308604771978354","article-title":"Glutaredoxins: Glutathione-Dependent Redox Enzymes with Functions Far Beyond a Simple Thioredoxin Backup System","volume":"6","author":"Fernandes","year":"2004","journal-title":"Antioxid. Redox Signal."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0076-6879(02)48630-2","article-title":"Redox Potential of GSH\/GSSG Couple: Assay and Biological Significance","volume":"348","author":"Jones","year":"2002","journal-title":"Methods Enzym."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/0076-6879(95)52007-4","article-title":"Diversity of Glutathione Peroxidases","volume":"252","author":"Ursini","year":"1995","journal-title":"Methods Enzym."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/s41419-022-05082-3","article-title":"Thiostrepton Induces Ferroptosis in Pancreatic Cancer Cells through STAT3\/GPX4 Signalling","volume":"13","author":"Zhang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.freeradbiomed.2018.10.426","article-title":"Nrf2 Inhibition Reverses Resistance to GPX4 Inhibitor-Induced Ferroptosis in Head and Neck Cancer","volume":"129","author":"Shin","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s10616-022-00545-z","article-title":"Silencing TRPM2 Enhanced Erastin- and RSL3-Induced Ferroptosis in Gastric Cancer Cells through Destabilizing HIF-1\u03b1 and Nrf2 Proteins","volume":"74","author":"Li","year":"2022","journal-title":"Cytotechnology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2174\/187152011795677544","article-title":"Superoxide Dismutase in Redox Biology: The Roles of Superoxide and Hydrogen Peroxide","volume":"11","author":"Buettner","year":"2011","journal-title":"Anti-Cancer Agents Med. Chem. Anti-Cancer Agents"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Nie, S., Shi, Z., Shi, M., Li, H., Qian, X., Peng, C., Ding, X., Zhang, S., Lv, Y., and Wang, L. (2022). PPAR\u03b3\/SOD2 Protects Against Mitochondrial ROS-Dependent Apoptosis via Inhibiting ATG4D-Mediated Mitophagy to Promote Pancreatic Cancer Proliferation. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.745554"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Miao, Y., Chen, Y., Xue, F., Liu, K., Zhu, B., Gao, J., Yin, J., Zhang, C., and Li, G. (2022). Contribution of Ferroptosis and GPX4\u2032s Dual Functions to Osteoarthritis Progression. eBioMedicine, 76.","DOI":"10.1016\/j.ebiom.2022.103847"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.bbrc.2016.08.124","article-title":"Identification of ACSL4 as a Biomarker and Contributor of Ferroptosis","volume":"478","author":"Yuan","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cmet.2008.07.005","article-title":"Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12\/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death","volume":"8","author":"Seiler","year":"2008","journal-title":"Cell Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.chembiol.2018.11.016","article-title":"Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State","volume":"26","author":"Magtanong","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Ye, Z., Zhuo, Q., Hu, Q., Xu, X., Liu, M., Zhang, Z., Xu, W., Liu, W., Fan, G., and Qin, Y. (2021). FBW7-NRA41-SCD1 Axis Synchronously Regulates Apoptosis and Ferroptosis in Pancreatic Cancer Cells. Redox Biol., 38.","DOI":"10.1016\/j.redox.2020.101807"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5355","DOI":"10.1158\/0008-5472.CAN-19-0369","article-title":"Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death","volume":"79","author":"Tesfay","year":"2019","journal-title":"Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/s41587-019-0055-9","article-title":"The International Cancer Genome Consortium Data Portal","volume":"37","author":"Zhang","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2008). Comprehensive Genomic Characterization Defines Human Glioblastoma Genes and Core Pathways. Nature, 455, 1061\u20131068.","DOI":"10.1038\/nature07385"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/nm.2311","article-title":"Taming the Dragon: Genomic Biomarkers to Individualize the Treatment of Cancer","volume":"17","author":"Majewski","year":"2011","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic Analyses Identify Molecular Subtypes of Pancreatic Cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41575-021-00470-0","article-title":"Early Detection of Pancreatic Cancer Using DNA-Based Molecular Approaches","volume":"18","author":"Singhi","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Martinez-Useros, J., Martin-Galan, M., and Garcia-Foncillas, J. (2021). The Match between Molecular Subtypes, Histology and Microenvironment of Pancreatic Cancer and Its Relevance for Chemoresistance. Cancers, 13.","DOI":"10.3390\/cancers13020322"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nature16064","article-title":"Epithelial-to-Mesenchymal Transition Is Dispensable for Metastasis but Induces Chemoresistance in Pancreatic Cancer","volume":"527","author":"Zheng","year":"2015","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1053\/j.gastro.2020.06.050","article-title":"TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines","volume":"159","author":"Jiang","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41419-021-03438-9","article-title":"Loss-of-Function of P53 Isoform \u0394113p53 Accelerates Brain Aging in Zebrafish","volume":"12","author":"Zhao","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1038\/nm1320","article-title":"The Antioxidant Function of the P53 Tumor Suppressor","volume":"11","author":"Sablina","year":"2005","journal-title":"Nat. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1158\/0008-5472.CAN-08-2320","article-title":"Tumor Protein 53-Induced Nuclear Protein 1 Is a Major Mediator of P53 Antioxidant Function","volume":"69","author":"Cano","year":"2009","journal-title":"Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"802","DOI":"10.15252\/emmm.201404318","article-title":"Defects in Mitophagy Promote Redox-Driven Metabolic Syndrome in the Absence of TP53INP1","volume":"7","author":"Seillier","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cmet.2012.12.002","article-title":"Sestrins Activate Nrf2 by Promoting P62-Dependent Autophagic Degradation of Keap1 and Prevent Oxidative Liver Damage","volume":"17","author":"Bae","year":"2013","journal-title":"Cell Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.molcel.2009.04.029","article-title":"Direct Interaction between Nrf2 and P21(Cip1\/WAF1) Upregulates the Nrf2-Mediated Antioxidant Response","volume":"34","author":"Chen","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_89","first-page":"5578","article-title":"Mutant p53R273H Attenuates the Expression of Phase 2 Detoxifying Enzymes and Promotes the Survival of Cells with High Levels of Reactive Oxygen Species","volume":"125","author":"Kalo","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.ccr.2009.03.022","article-title":"A Gene Expression Signature Associated with \u201cK-Ras Addiction\u201d Reveals Regulators of EMT and Tumor Cell Survival","volume":"15","author":"Singh","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"8788","DOI":"10.1073\/pnas.1003428107","article-title":"Mitochondrial Metabolism and ROS Generation Are Essential for Kras-Mediated Tumorigenicity","volume":"107","author":"Weinberg","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1080\/21541248.2016.1192714","article-title":"KRas, ROS and the Initiation of Pancreatic Cancer","volume":"8","author":"Storz","year":"2017","journal-title":"Small GTPases"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1016\/j.celrep.2016.02.029","article-title":"Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions","volume":"14","author":"Liou","year":"2016","journal-title":"Cell Rep."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"D\u00f6ppler, H., Liou, G.-Y., and Storz, P. (2013). Downregulation of TRAF2 Mediates NIK-Induced Pancreatic Cancer Cell Proliferation and Tumorigenicity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053676"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3389\/fonc.2018.00617","article-title":"Metabolic Dependencies in Pancreatic Cancer","volume":"8","author":"Zarei","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature10189","article-title":"Oncogene-Induced Nrf2 Transcription Promotes ROS Detoxification and Tumorigenesis","volume":"475","author":"DeNicola","year":"2011","journal-title":"Nature"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1136\/gutjnl-2012-304287","article-title":"Nr5a2 Maintains Acinar Cell Differentiation and Constrains Oncogenic Kras-Mediated Pancreatic Neoplastic Initiation","volume":"63","author":"Morris","year":"2014","journal-title":"Gut"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1242\/dev.109405","article-title":"The Nuclear Hormone Receptor Family Member NR5A2 Controls Aspects of Multipotent Progenitor Cell Formation and Acinar Differentiation during Pancreatic Organogenesis","volume":"141","author":"Hale","year":"2014","journal-title":"Development"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1242\/jcs.041061","article-title":"Mitochondrial Diacylglycerol Initiates Protein-Kinase D1-Mediated ROS Signaling","volume":"122","author":"Cowell","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ccr.2012.07.024","article-title":"EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis","volume":"22","author":"Ardito","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41575-020-0300-1","article-title":"Pancreatic Cancer Stroma: An Update on Therapeutic Targeting Strategies","volume":"17","author":"Hosein","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e000778","DOI":"10.1136\/jitc-2020-000778","article-title":"M1hot Tumor-Associated Macrophages Boost Tissue-Resident Memory T Cells Infiltration and Survival in Human Lung Cancer","volume":"8","author":"Mellows","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1245\/s10434-015-4463-x","article-title":"Molecular Pathogenesis and Targeted Therapy of Pancreatic Cancer","volume":"23","author":"Tanaka","year":"2016","journal-title":"Ann. Surg. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, Biology and Role in Disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5107","DOI":"10.7150\/thno.44705","article-title":"Combinative Treatment of \u03b2-Elemene and Cetuximab Is Sensitive to KRAS Mutant Colorectal Cancer Cells by Inducing Ferroptosis and Inhibiting Epithelial-Mesenchymal Transformation","volume":"10","author":"Chen","year":"2020","journal-title":"Theranostics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41419-021-04367-3","article-title":"Cetuximab Promotes RSL3-Induced Ferroptosis by Suppressing the Nrf2\/HO-1 Signalling Pathway in KRAS Mutant Colorectal Cancer","volume":"12","author":"Yang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature14344","article-title":"Ferroptosis as a P53-Mediated Activity during Tumour Suppression","volume":"520","author":"Jiang","year":"2015","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cell.2006.05.036","article-title":"TIGAR, a P53-Inducible Regulator of Glycolysis and Apoptosis","volume":"126","author":"Bensaad","year":"2006","journal-title":"Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"7455","DOI":"10.1073\/pnas.1001006107","article-title":"Glutaminase 2, a Novel P53 Target Gene Regulating Energy Metabolism and Antioxidant Function","volume":"107","author":"Hu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"14844","DOI":"10.1038\/ncomms14844","article-title":"Inhibiting the System xC-\/Glutathione Axis Selectively Targets Cancers with Mutant-P53 Accumulation","volume":"8","author":"Liu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1146\/annurev-immunol-073119-095439","article-title":"Caspases in Cell Death, Inflammation, and Pyroptosis","volume":"38","author":"Kesavardhana","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.phrs.2008.05.002","article-title":"Polyunsaturated Fatty Acids as Antioxidants","volume":"57","author":"Richard","year":"2008","journal-title":"Pharmacol. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"E4966","DOI":"10.1073\/pnas.1603244113","article-title":"Peroxidation of Polyunsaturated Fatty Acids by Lipoxygenases Drives Ferroptosis","volume":"113","author":"Yang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Ill\u00e9s, E., Patra, S.G., Marks, V., Mizrahi, A., and Meyerstein, D. (2020). The FeII(Citrate) Fenton Reaction under Physiological Conditions. J. Inorg. Biochem., 206.","DOI":"10.1016\/j.jinorgbio.2020.111018"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Lopes, T.J.S., Luganskaja, T., Vuji\u0107 Spasi\u0107, M., Hentze, M.W., Muckenthaler, M.U., Sch\u00fcmann, K., and Reich, J.G. (2010). Systems Analysis of Iron Metabolism: The Network of Iron Pools and Fluxes. BMC Syst. Biol., 4.","DOI":"10.1186\/1752-0509-4-112"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.freeradbiomed.2007.08.006","article-title":"Iron Chelators Can Protect against Oxidative Stress through Ferryl Heme Reduction","volume":"44","author":"Reeder","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"109235","DOI":"10.1016\/j.celrep.2021.109235","article-title":"The Glutathione Peroxidase Gpx4 Prevents Lipid Peroxidation and Ferroptosis to Sustain Treg Cell Activation and Suppression of Antitumor Immunity","volume":"35","author":"Xu","year":"2021","journal-title":"Cell Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.4103\/eus.eus_60_17","article-title":"Pancreatic Ductal Adenocarcinoma Epidemiology and Risk Assessment: Could We Prevent? Possibility for an Early Diagnosis","volume":"6","author":"Bekkali","year":"2017","journal-title":"Endosc. Ultrasound"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Tian, N., Wu, D., Zhu, L., Zeng, M., Li, J., and Wang, X. (2022). A Predictive Model for Recurrence after Upfront Surgery in Patients with Resectable Pancreatic Ductal Adenocarcinoma (PDAC) by Using Preoperative Clinical Data and CT Characteristics. BMC Med. Imaging, 22.","DOI":"10.1186\/s12880-022-00823-4"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1097\/SLA.0000000000002734","article-title":"Defining and Predicting Early Recurrence in 957 Patients With Resected Pancreatic Ductal Adenocarcinoma","volume":"269","author":"Groot","year":"2019","journal-title":"Ann. Surg."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"e113","DOI":"10.1016\/j.lpm.2019.02.030","article-title":"Epidemiology and Burden of Pancreatic Cancer","volume":"48","author":"Maisonneuve","year":"2019","journal-title":"La Presse M\u00e9dicale"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1158\/1535-7163.MCT-14-0420","article-title":"Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation","volume":"14","author":"Ju","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/13813450701531235","article-title":"Regulation of NADPH Oxidase Subunit P22(Phox) by NF-kB in Human Aortic Smooth Muscle Cells","volume":"113","author":"Manea","year":"2007","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.phrs.2008.09.003","article-title":"Dual Roles of Nrf2 in Cancer","volume":"58","author":"Lau","year":"2008","journal-title":"Pharmacol. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3109\/00498254.2014.942809","article-title":"A Comparison of Cardiomyocyte Cytotoxic Mechanisms for 5-Fluorouracil and Its pro-Drug Capecitabine","volume":"45","author":"Eskandari","year":"2015","journal-title":"Xenobiotica"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"34245","DOI":"10.1038\/srep34245","article-title":"Sanguisorba Officinalis L Synergistically Enhanced 5-Fluorouracil Cytotoxicity in Colorectal Cancer Cells by Promoting a Reactive Oxygen Species-Mediated, Mitochondria-Caspase-Dependent Apoptotic Pathway","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.2147\/OTT.S240803","article-title":"Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells","volume":"13","author":"Zhu","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"589","DOI":"10.7150\/ijbs.49514","article-title":"Inhibition of PI3K\/AKT Signaling via ROS Regulation Is Involved in Rhein-Induced Apoptosis and Enhancement of Oxaliplatin Sensitivity in Pancreatic Cancer Cells","volume":"17","author":"Liu","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_129","first-page":"8289","article-title":"Paclitaxel Suppresses Proliferation and Induces Apoptosis through Regulation of ROS and the AKT\/MAPK Signaling Pathway in Canine Mammary Gland Tumor Cells","volume":"17","author":"Ren","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41571-020-0341-y","article-title":"Targeting Apoptosis in Cancer Therapy","volume":"17","author":"Carneiro","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Dodson, M., Castro-Portuguez, R., and Zhang, D.D. (2019). NRF2 Plays a Critical Role in Mitigating Lipid Peroxidation and Ferroptosis. Redox Biol., 23.","DOI":"10.1016\/j.redox.2019.101107"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of Apoptosis Signalling Pathways by Reactive Oxygen Species","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1007\/s12011-016-0810-4","article-title":"Oxidative Damage Induced by Arsenic in Mice or Rats: A Systematic Review and Meta-Analysis","volume":"176","author":"Xu","year":"2017","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1097\/00006676-200308000-00011","article-title":"Arsenic Trioxide Induces Apoptosis in Pancreatic Cancer Cells via Changes in Cell Cycle, Caspase Activation, and GADD Expression","volume":"27","author":"Li","year":"2003","journal-title":"Pancreas"},{"key":"ref_135","first-page":"3065","article-title":"Arsenic Trioxide-Mediated Growth Inhibition in MC\/CAR Myeloma Cells via Cell Cycle Arrest in Association with Induction of Cyclin-Dependent Kinase Inhibitor, P21, and Apoptosis","volume":"60","author":"Park","year":"2000","journal-title":"Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ccell.2021.01.012","article-title":"Arsenic and an Old Place: Rescuing P53 Mutants in Cancer","volume":"39","author":"Loh","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13045-022-01368-3","article-title":"Oral Arsenic and Retinoic Acid for High-Risk Acute Promyelocytic Leukemia","volume":"15","author":"Ma","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1097\/COC.0b013e318178e4cd","article-title":"Arsenic Trioxide in Patients with Adenocarcinoma of the Pancreas Refractory to Gemcitabine: A Phase II Trial of the University of Chicago Phase II Consortium","volume":"31","author":"Kindler","year":"2008","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1126\/science.aaa5004","article-title":"Vitamin C Selectively Kills KRAS and BRAF Mutant Colorectal Cancer Cells by Targeting GAPDH","volume":"350","author":"Yun","year":"2015","journal-title":"Science"},{"key":"ref_140","first-page":"1011","article-title":"Piperlongumine Rapidly Induces the Death of Human Pancreatic Cancer Cells Mainly through the Induction of Ferroptosis","volume":"52","author":"Yamaguchi","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"517","DOI":"10.18632\/oncoscience.160","article-title":"Identification of Artesunate as a Specific Activator of Ferroptosis in Pancreatic Cancer Cells","volume":"2","author":"Eling","year":"2015","journal-title":"Oncoscience"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.chembiol.2019.01.008","article-title":"Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model","volume":"26","author":"Zhang","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nm.4232","article-title":"Systemic Depletion of L-Cyst(e)Ine with Cyst(e)Inase Increases Reactive Oxygen Species and Suppresses Tumor Growth","volume":"23","author":"Cramer","year":"2017","journal-title":"Nat. Med."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"865655","DOI":"10.3389\/fendo.2022.865655","article-title":"Platelet-Vesicles-Encapsulated RSL-3 Enable Anti-Angiogenesis and Induce Ferroptosis to Inhibit Pancreatic Cancer Progress","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Lee, W., Song, G., and Bae, H. (2022). Laminarin Attenuates ROS-Mediated Cell Migration and Invasiveness through Mitochondrial Dysfunction in Pancreatic Cancer Cells. Antioxidants, 11.","DOI":"10.3390\/antiox11091714"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Abdel Hadi, N., Reyes-Castellanos, G., and Carrier, A. (2021). Targeting Redox Metabolism in Pancreatic Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041534"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1042\/BCJ20180043","article-title":"Protein CoAlation and Antioxidant Function of Coenzyme A in Prokaryotic Cells","volume":"475","author":"Tsuchiya","year":"2018","journal-title":"Biochem. J."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.abb.2007.08.008","article-title":"Pre-Steady State Kinetic Characterization of Human Peroxiredoxin 5: Taking Advantage of Trp84 Fluorescence Increase upon Oxidation","volume":"467","author":"Trujillo","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1093\/gerona\/glp132","article-title":"Mice Deficient in Both Mn Superoxide Dismutase and Glutathione Peroxidase-1 Have Increased Oxidative Damage and a Greater Incidence of Pathology but No Reduction in Longevity","volume":"64A","author":"Zhang","year":"2009","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1158\/0008-5472.CAN-12-3150","article-title":"Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma","volume":"73","author":"Barrett","year":"2013","journal-title":"Cancer Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ccell.2019.12.012","article-title":"Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer","volume":"37","author":"Cheung","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"388","DOI":"10.2174\/1568009622666211231140623","article-title":"The Potential of Natural Products in the Treatment of Triple-Negative Breast Cancer","volume":"22","author":"Ke","year":"2022","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10637-008-9207-3","article-title":"Novel Herbal Flavonoids Promote Apoptosis but Differentially Induce Cell Cycle Arrest in Human Colon Cancer Cell","volume":"28","author":"Auyeung","year":"2010","journal-title":"Investig. New Drugs"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"31554","DOI":"10.18632\/oncotarget.15767","article-title":"\u03b4-Tocotrienol, a Natural Form of Vitamin E, Inhibits Pancreatic Cancer Stem-like Cells and Prevents Pancreatic Cancer Metastasis","volume":"8","author":"Husain","year":"2017","journal-title":"Oncotarget"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"4825","DOI":"10.1038\/onc.2012.493","article-title":"Inhibition of the Nrf2 Transcription Factor by the Alkaloid Trigonelline Renders Pancreatic Cancer Cells More Susceptible to Apoptosis through Decreased Proteasomal Gene Expression and Proteasome Activity","volume":"32","author":"Arlt","year":"2013","journal-title":"Oncogene"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Zhang, W., Zhu, Y., Yu, H., Liu, X., Jiao, B., and Lu, X. (2021). Libertellenone H, a Natural Pimarane Diterpenoid, Inhibits Thioredoxin System and Induces ROS-Mediated Apoptosis in Human Pancreatic Cancer Cells. Molecules, 26.","DOI":"10.3390\/molecules26020315"},{"key":"ref_157","first-page":"1581","article-title":"Inhibition of Cancer Cell Growth in Gemcitabine-Resistant Pancreatic Carcinoma by Mangiferin Phytochemical Involves Induction of Autophagy, Endogenous ROS Production, Cell Cycle Disruption, Mitochondrial Mediated Apoptosis and Suppression of Cancer Cell Migration and Invasion","volume":"24","author":"Yu","year":"2019","journal-title":"J. BUON"},{"key":"ref_158","first-page":"177","article-title":"Combination Treatment with Oxaliplatin and Mangiferin Causes Increased Apoptosis and Downregulation of NF\u03baB in Cancer Cell Lines","volume":"8","year":"2011","journal-title":"Afr. J. Tradit. Complement. Altern. Med."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1111\/bph.15350","article-title":"Quercetin Induces P53-Independent Cancer Cell Death through Lysosome Activation by the Transcription Factor EB and Reactive Oxygen Species-Dependent Ferroptosis","volume":"178","author":"Wang","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"968","DOI":"10.3892\/or.2016.4867","article-title":"Combined Treatment with Cotylenin A and Phenethyl Isothiocyanate Induces Strong Antitumor Activity Mainly through the Induction of Ferroptotic Cell Death in Human Pancreatic Cancer Cells","volume":"36","author":"Kasukabe","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"841","DOI":"10.3892\/ijo.2014.2760","article-title":"Cotylenin A and Arsenic Trioxide Cooperatively Suppress Cell Proliferation and Cell Invasion Activity in Human Breast Cancer Cells","volume":"46","author":"Kasukabe","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41556-020-0461-8","article-title":"Energy-Stress-Mediated AMPK Activation Inhibits Ferroptosis","volume":"22","author":"Lee","year":"2020","journal-title":"Nat. Cell Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14979\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:02:32Z","timestamp":1760130152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,7]]},"references-count":162,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914979"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914979","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,7]]}}}