{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:07:54Z","timestamp":1784542074091,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ferroptosis has emerged as a promising strategy to overcome resistance to conventional cancer therapies. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia, therapy resistance, and an immunosuppressive microenvironment. Although hypoxia is likely to influence ferroptosis susceptibility and the associated inflammatory pathways that regulate antitumor immunity, their impact on ferroptosis sensitivity and innate immune responses remains poorly understood. In this study, we investigated the effects of hypoxia on the induction of ferroptosis and immune-related signaling in PDAC cell lines. We examined how hypoxia affects the responses of Panc-1, BxPC3, and Capan-1 cells to the ferroptosis inducers RAS-selective lethal 3 (RSL3)\/Imidazole ketone erastin (IKE) under normoxic and hypoxic (0.1% O2) conditions. Cell viability assays were used to assess ferroptosis sensitivity, and rescue experiments were performed using liproxstatin-1 (LIP). Gene expression analysis was conducted to evaluate changes in immune, interferon, inflammatory, and hypoxia-related genes following ferroptosis induction. Panc-1 cells were the most sensitive, whereas Capan-1 cells were resistant, particularly under hypoxia. Ferroptosis triggered cell line-specific responses involving interferon signaling, inflammation, and stress pathways. Panc-1 cells showed over-expression of RIG-I, MAVS, IRF3\/7\/9, STAT1\/2, and CXCL10, particularly under hypoxia, indicating activation of Type I interferon (IFN)-associated transcriptional program. BxPC3 cells demonstrated broader cytokine induction, including IL-8, CCL2, CXCL2, GM-CSF, and IL-11, whereas Capan-1 cells were minimally responsive. Hypoxia also increased ANGPTL4 and GDF15 expression following ferroptosis induction. These findings show that hypoxia differentially affects ferroptosis sensitivity and immune responses in PDAC, revealing complex interactions among ferroptosis, innate immunity, and the tumor microenvironment.<\/jats:p>","DOI":"10.3390\/ijms27146397","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia Differentially Regulates Ferroptosis Sensitivity and Tumor Cell-Intrinsic Type I Interferon Signaling in Pancreatic Ductal Adenocarcinoma Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8044-532X","authenticated-orcid":false,"given":"Shubhankar","family":"Das","sequence":"first","affiliation":[{"name":"Thumbay Research Institute for Precision Medicine, Gulf Medical University, University Street, Street #1, Ajman P.O. Box 4184, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayda Shah","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Thumbay Research Institute for Precision Medicine, Gulf Medical University, University Street, Street #1, Ajman P.O. Box 4184, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salem","family":"Chouaib","sequence":"additional","affiliation":[{"name":"Thumbay Research Institute for Precision Medicine, Gulf Medical University, University Street, Street #1, Ajman P.O. Box 4184, United Arab Emirates"},{"name":"Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, University Paris-Saclay, INSERM UMR 1186, F-94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e214708","DOI":"10.1001\/jamanetworkopen.2021.4708","article-title":"Estimated Projection of US Cancer Incidence and Death to 2040","volume":"4","author":"Rahib","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S0140-6736(10)62307-0","article-title":"Pancreatic cancer","volume":"378","author":"Vincent","year":"2011","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1158\/0008-5472.CAN-18-3962","article-title":"The Tumor Microenvironment Innately Modulates Cancer Progression","volume":"79","author":"Hinshaw","year":"2019","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.trecan.2018.04.001","article-title":"Immunotherapy and Prevention of Pancreatic Cancer","volume":"4","author":"Morrison","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1126\/science.aaw9872","article-title":"Cysteine depletion induces pancreatic tumor ferroptosis in mice","volume":"368","author":"Badgley","year":"2020","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105292","DOI":"10.1016\/j.critrevonc.2026.105292","article-title":"Immunotherapy and ferroptosis regulation in thyroid cancer: Novel strategies and future perspectives","volume":"222","author":"Wang","year":"2026","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Xu, Y., Ge, M., Xu, Y., and Yin, K. (2025). Ferroptosis: A novel perspective on tumor immunotherapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1524711"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Battaglia, A.M., Chirillo, R., Aversa, I., Sacco, A., Costanzo, F., and Biamonte, F. (2020). Ferroptosis and Cancer: Mitochondria Meet the \u201cIron Maiden\u201d Cell Death. Cells, 9.","DOI":"10.3390\/cells9061505"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.immuni.2024.03.019","article-title":"Ironing out the role of ferroptosis in immunity","volume":"57","author":"Bell","year":"2024","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.it.2016.12.004","article-title":"Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways","volume":"38","author":"Zevini","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/j.cell.2016.11.022","article-title":"Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade","volume":"167","author":"Benci","year":"2016","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41392-025-02499-y","article-title":"Pancreatic cancer: Molecular pathogenesis and emerging therapeutic strategies","volume":"11","author":"Rozengurt","year":"2026","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0360-3016(00)00803-8","article-title":"Pancreatic tumors show high levels of hypoxia","volume":"48","author":"Koong","year":"2000","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.tibs.2025.06.005","article-title":"The HIF axes in cancer: Angiogenesis, metabolism, and immune-modulation","volume":"50","author":"Koh","year":"2025","journal-title":"Trends Biochem. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111328","DOI":"10.1016\/j.cellsig.2024.111328","article-title":"Hypoxia and ferroptosis","volume":"122","author":"Liu","year":"2024","journal-title":"Cell Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5245","DOI":"10.1158\/0008-5472.CAN-19-2306","article-title":"Hypoxia Induces Transcriptional and Translational Downregulation of the Type I IFN Pathway in Multiple Cancer Cell Types","volume":"80","author":"Miar","year":"2020","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.1172\/JCI84433","article-title":"Hypoxia-dependent regulation of inflammatory pathways in immune cells","volume":"126","author":"Taylor","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/MPA.0b013e3181c15963","article-title":"Phenotype and genotype of pancreatic cancer cell lines","volume":"39","author":"Deer","year":"2010","journal-title":"Pancreas"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1007\/s004280100474","article-title":"Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4\/Smad4","volume":"439","author":"Moore","year":"2001","journal-title":"Virchows Arch."},{"key":"ref_25","first-page":"3126","article-title":"Abrogation of the Rb\/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas","volume":"57","author":"Schutte","year":"1997","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Korbecki, J., Kojder, K., Barczak, K., Siminska, D., Gutowska, I., Chlubek, D., and Baranowska-Bosiacka, I. (2020). Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor-A Literature Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165647"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ramos, P., Shi, Q., Kleberg, J., Maharjan, C.K., Zhang, W., and Kolb, R. (2025). ANGPTL4: A Comprehensive Review of 25 Years of Research. Cancers, 17.","DOI":"10.3390\/cancers17142364"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/s41401-023-01199-z","article-title":"SMAD4 endows TGF-beta1-induced highly invasive tumor cells with ferroptosis vulnerability in pancreatic cancer","volume":"45","author":"Chen","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Karpiuk, K.R., Mlynarczyk, G., Matowicka-Karna, J., and Darewicz, B. (2025). Emerging Biomarkers in Urological Cancers: Angiogenesis and Damage-Associated Molecular Pattern Signaling. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26189130"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s41586-019-1705-2","article-title":"The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis","volume":"575","author":"Bersuker","year":"2019","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s41586-021-03539-7","article-title":"DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer","volume":"593","author":"Mao","year":"2021","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s13238-020-00789-5","article-title":"Cystine transporter SLC7A11\/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy","volume":"12","author":"Koppula","year":"2021","journal-title":"Protein Cell"},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1038\/s41418-025-01517-4","article-title":"An atlas of ferroptosis-induced secretomes","volume":"32","author":"Yapici","year":"2025","journal-title":"Cell Death Differ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/s41419-026-08604-5","article-title":"IFI16 is essential to linking DNA damage and ferroptosis in acute kidney injury","volume":"17","author":"Qiao","year":"2026","journal-title":"Cell Death Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.tcb.2020.02.009","article-title":"Emerging Mechanisms and Disease Relevance of Ferroptosis","volume":"30","author":"Stockwell","year":"2020","journal-title":"Trends Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1089\/ars.2009.2597","article-title":"Generation and biological activities of oxidized phospholipids","volume":"12","author":"Bochkov","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e001369","DOI":"10.1136\/jitc-2020-001369","article-title":"Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity","volume":"8","author":"Efimova","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/s41419-024-07244-x","article-title":"Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications","volume":"15","author":"Zheng","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","article-title":"CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation-A target for novel cancer therapy","volume":"63","author":"Tokunaga","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"116823","DOI":"10.1016\/j.microc.2026.116823","article-title":"Electrochemical sensor analyzing ANGPTL4 promotes M2 polarization of lung adenocarcinoma tumor-associated macrophages: Inhibiting ferroptosis through the NF-\u03baB-induced SLC7A11 transcription","volume":"221","author":"Qin","year":"2026","journal-title":"Microchem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cytogfr.2026.01.004","article-title":"GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance","volume":"88","author":"Lu","year":"2026","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature10138","article-title":"CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis","volume":"475","author":"Qian","year":"2011","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.ccr.2012.04.025","article-title":"Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer","volume":"21","author":"Bayne","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"BSR20204312","DOI":"10.1042\/BSR20204312","article-title":"CXCL2\/10\/12\/14 are prognostic biomarkers and correlated with immune infiltration in hepatocellular carcinoma","volume":"41","author":"Lin","year":"2021","journal-title":"Biosci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6735","DOI":"10.1158\/1078-0432.CCR-07-4843","article-title":"The interleukin-8 pathway in cancer","volume":"14","author":"Waugh","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"441","DOI":"10.2217\/imt.15.17","article-title":"IL-11 signaling as a therapeutic target for cancer","volume":"7","author":"Putoczki","year":"2015","journal-title":"Immunotherapy"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-019-1170-y","article-title":"CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy","volume":"569","author":"Wang","year":"2019","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1016\/j.gendis.2023.02.034","article-title":"Targeting hypoxia-induced CBS expression inhibits breast cancer stem cells through the induction of ferroptosis","volume":"10","author":"Wei","year":"2023","journal-title":"Genes Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.molcel.2026.03.007","article-title":"The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer","volume":"86","author":"Hubbi","year":"2026","journal-title":"Mol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.3390\/cancers17121988","article-title":"Evofosfamide Enhances Sensitivity of Breast Cancer Cells to Apoptosis and Natural-Killer-Cell-Mediated Cytotoxicity Under Hypoxic Conditions","volume":"17","author":"Das","year":"2025","journal-title":"Cancers"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1021\/acscentsci.7b00028","article-title":"On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death","volume":"3","author":"Zilka","year":"2017","journal-title":"ACS Cent. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:37:31Z","timestamp":1784540251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,18]]},"references-count":52,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146397"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146397","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,18]]}}}