{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:30:00Z","timestamp":1791639000037,"version":"4.3.4"},"reference-count":63,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Welsh Government\u2019s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and BCUHB","award":["2504"],"award-info":[{"award-number":["2504"]}]},{"name":"Welsh Government\u2019s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and BCUHB","award":["2527"],"award-info":[{"award-number":["2527"]}]},{"name":"Welsh Government\u2019s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and BCUHB","award":["2018-S04"],"award-info":[{"award-number":["2018-S04"]}]},{"name":"Welsh Government\u2019s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and BCUHB","award":["1050795978"],"award-info":[{"award-number":["1050795978"]}]},{"name":"Welsh Government\u2019s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and BCUHB","award":["R21CA263133"],"award-info":[{"award-number":["R21CA263133"]}]},{"name":"Cancer Research Wales PhD studentship","award":["2504"],"award-info":[{"award-number":["2504"]}]},{"name":"Cancer Research Wales PhD studentship","award":["2527"],"award-info":[{"award-number":["2527"]}]},{"name":"Cancer Research Wales PhD studentship","award":["2018-S04"],"award-info":[{"award-number":["2018-S04"]}]},{"name":"Cancer Research Wales PhD studentship","award":["1050795978"],"award-info":[{"award-number":["1050795978"]}]},{"name":"Cancer Research Wales PhD studentship","award":["R21CA263133"],"award-info":[{"award-number":["R21CA263133"]}]},{"name":"Cancer Research Wales Fellowship","award":["2504"],"award-info":[{"award-number":["2504"]}]},{"name":"Cancer Research Wales Fellowship","award":["2527"],"award-info":[{"award-number":["2527"]}]},{"name":"Cancer Research Wales Fellowship","award":["2018-S04"],"award-info":[{"award-number":["2018-S04"]}]},{"name":"Cancer Research Wales Fellowship","award":["1050795978"],"award-info":[{"award-number":["1050795978"]}]},{"name":"Cancer Research Wales Fellowship","award":["R21CA263133"],"award-info":[{"award-number":["R21CA263133"]}]},{"name":"Tuberous Sclerosis Association","award":["2504"],"award-info":[{"award-number":["2504"]}]},{"name":"Tuberous Sclerosis Association","award":["2527"],"award-info":[{"award-number":["2527"]}]},{"name":"Tuberous Sclerosis Association","award":["2018-S04"],"award-info":[{"award-number":["2018-S04"]}]},{"name":"Tuberous Sclerosis Association","award":["1050795978"],"award-info":[{"award-number":["1050795978"]}]},{"name":"Tuberous Sclerosis Association","award":["R21CA263133"],"award-info":[{"award-number":["R21CA263133"]}]},{"name":"King Fahd Security College\/Ministry of Interior\/Saudi Arabia","award":["2504"],"award-info":[{"award-number":["2504"]}]},{"name":"King Fahd Security College\/Ministry of Interior\/Saudi Arabia","award":["2527"],"award-info":[{"award-number":["2527"]}]},{"name":"King Fahd Security College\/Ministry of Interior\/Saudi Arabia","award":["2018-S04"],"award-info":[{"award-number":["2018-S04"]}]},{"name":"King Fahd Security College\/Ministry of Interior\/Saudi Arabia","award":["1050795978"],"award-info":[{"award-number":["1050795978"]}]},{"name":"King Fahd Security College\/Ministry of Interior\/Saudi Arabia","award":["R21CA263133"],"award-info":[{"award-number":["R21CA263133"]}]},{"name":"Health and Care Research Wales (Wales Gene Park)","award":["2504"],"award-info":[{"award-number":["2504"]}]},{"name":"Health and Care Research Wales (Wales Gene Park)","award":["2527"],"award-info":[{"award-number":["2527"]}]},{"name":"Health and Care Research Wales (Wales Gene Park)","award":["2018-S04"],"award-info":[{"award-number":["2018-S04"]}]},{"name":"Health and Care Research Wales (Wales Gene Park)","award":["1050795978"],"award-info":[{"award-number":["1050795978"]}]},{"name":"Health and Care Research Wales (Wales Gene Park)","award":["R21CA263133"],"award-info":[{"award-number":["R21CA263133"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers.<\/jats:p>","DOI":"10.3390\/cancers17162714","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T08:02:44Z","timestamp":1755763364000},"page":"2714","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Targeting NRF2 and FSP1 to Overcome Ferroptosis Resistance in TSC2-Deficient and Cancer Cells"],"prefix":"10.3390","volume":"17","author":[{"given":"Tasmia","family":"Tahsin","sequence":"first","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Faculty of Medicine, Health & Life Science, Swansea University, Swansea SA2 8PP, UK"},{"name":"Maelor Academic Unit of Medical & Surgical Sciences (MAUMSS), Betsi Cadwaladr University Health Board (BCUHB), Faculty of Social & Life Sciences, Wrexham University, Gwenfro Buildings, Technology Park, Wrexham LL13 7YP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4490-2972","authenticated-orcid":false,"given":"Darius K.","family":"McPhail","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse D.","family":"Champion","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A. M.","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine L.","family":"Hilditch","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Faris-Orr","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Calver","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0590-9462","authenticated-orcid":false,"given":"James G.","family":"Cronin","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Faculty of Medicine, Health & Life Science, Swansea University, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Mareque-Rivas","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Swansea University, Singleton Park, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3344-3150","authenticated-orcid":false,"given":"Darren W.","family":"Sexton","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6558-9037","authenticated-orcid":false,"given":"Stephen F\u00f4n","family":"Hughes","sequence":"additional","affiliation":[{"name":"Maelor Academic Unit of Medical & Surgical Sciences (MAUMSS), Betsi Cadwaladr University Health Board (BCUHB), Faculty of Social & Life Sciences, Wrexham University, Gwenfro Buildings, Technology Park, Wrexham LL13 7YP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2562-3461","authenticated-orcid":false,"given":"Robert Steven","family":"Conlan","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School, Faculty of Medicine, Health & Life Science, Swansea University, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Mark","family":"Davies","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5577-4631","authenticated-orcid":false,"given":"Andrew R.","family":"Tee","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1038\/s12276-023-01069-y","article-title":"Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis","volume":"55","author":"Lee","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/bs.vh.2022.09.002","article-title":"The antioxidant glutathione","volume":"121","year":"2023","journal-title":"Vitam. Horm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: Past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kuang, F., Liu, J., Tang, D., and Kang, R. (2020). Oxidative Damage and Antioxidant Defense in Ferroptosis. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.586578"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"165","DOI":"10.14348\/molcells.2023.0005","article-title":"Anti-Ferroptotic Effects of Nrf2: Beyond the Antioxidant Response","volume":"46","author":"Shakya","year":"2023","journal-title":"Mol. Cells"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chiang, S.K., Chen, S.E., and Chang, L.C. (2018). A Dual Role of Heme Oxygenase-1 in Cancer Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010039"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1158\/0008-5472.CAN-20-2017","article-title":"Iron and Cancer: 2020 Vision","volume":"80","author":"Torti","year":"2020","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, X., Li, X., Xia, R., and Zhang, H.S. (2024). Ferroptosis resistance in cancer: Recent advances and future perspectives. Biochem. Pharmacol., 219.","DOI":"10.1016\/j.bcp.2023.115933"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13571","DOI":"10.1073\/pnas.202476899","article-title":"Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling","volume":"99","author":"Tee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0960-9822(03)00506-2","article-title":"Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb","volume":"13","author":"Tee","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41417-020-0182-y","article-title":"Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death","volume":"28","author":"Liu","year":"2021","journal-title":"Cancer Gene Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1042\/BST0370217","article-title":"A complex interplay between Akt, TSC2 and the two mTOR complexes","volume":"37","author":"Huang","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/s41467-021-21841-w","article-title":"mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31189","DOI":"10.1073\/pnas.2017152117","article-title":"Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis","volume":"117","author":"Yi","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/j.chembiol.2022.10.006","article-title":"Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein","volume":"29","author":"Armenta","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1172\/JCI200317222","article-title":"Loss of Tsc1\/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR","volume":"112","author":"Zhang","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8470","DOI":"10.1038\/sj.onc.1205962","article-title":"Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration","volume":"21","author":"Astrinidis","year":"2002","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"L694","DOI":"10.1152\/ajplung.00204.2003","article-title":"Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways","volume":"286","author":"Yu","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15816","DOI":"10.1038\/ncomms15816","article-title":"The genomic landscape of tuberous sclerosis complex","volume":"8","author":"Martin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1038\/onc.2010.603","article-title":"Targeting the Akt\/mTOR pathway in Brca1-deficient cancers","volume":"30","author":"Xiang","year":"2011","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ygyno.2004.11.051","article-title":"Activation of PI3K\/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line","volume":"97","author":"Lee","year":"2005","journal-title":"Gynecol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/onc.2015.179","article-title":"Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP","volume":"35","author":"Ricoult","year":"2016","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: An ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinform."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinform."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of nrf2 in oxidative stress and toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5913","DOI":"10.1038\/s41388-018-0381-2","article-title":"Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir-bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death","volume":"37","author":"Johnson","year":"2018","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"737","DOI":"10.4161\/auto.7.7.15491","article-title":"ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding","volume":"7","author":"Dunlop","year":"2011","journal-title":"Autophagy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"616","DOI":"10.3724\/abbs.2024165","article-title":"Mechanism of RSL3-induced ferroptotic cell death in HT22 cells: Crucial role of protein disulfide isomerase","volume":"57","author":"Hou","year":"2024","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/s41392-023-01606-1","article-title":"Targeting ferroptosis opens new avenues for the development of novel therapeutics","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yuk, H., Abdullah, M., Kim, D.H., Lee, H., and Lee, S.J. (2021). Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma. Antioxidants, 10.","DOI":"10.3390\/antiox10091347"},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nature06322","article-title":"mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex","volume":"450","author":"Cunningham","year":"2007","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.celrep.2016.09.054","article-title":"Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex","volume":"17","author":"Saffari","year":"2016","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1073\/pnas.88.9.3671","article-title":"Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1","volume":"88","author":"Smiley","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Endale, H.T., Tesfaye, W., and Mengstie, T.A. (2023). ROS induced lipid peroxidation and their role in ferroptosis. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1226044"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1084\/jem.20081297","article-title":"TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species","volume":"205","author":"Chen","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5926","DOI":"10.1523\/JNEUROSCI.0778-09.2009","article-title":"Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner","volume":"29","author":"Kramvis","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.18632\/oncotarget.28301","article-title":"FSP1, a novel KEAP1\/NRF2 target gene regulating ferroptosis and radioresistance in lung cancers","volume":"13","author":"Emmanuel","year":"2022","journal-title":"Oncotarget"},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.tibs.2008.12.008","article-title":"NRF2 and KEAP1 mutations: Permanent activation of an adaptive response in cancer","volume":"34","author":"Hayes","year":"2009","journal-title":"Trends Biochem. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.molmed.2023.05.013","article-title":"FSP1: A key regulator of ferroptosis","volume":"29","author":"Li","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, L., Qiu, C., Hou, M., Wang, X., Huang, C., Zou, J., Liu, T., and Qu, J. (2021). Ferroptosis in Ovarian Cancer: A Novel Therapeutic Strategy. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.665945"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Liu, Y., Hu, Y., Jiang, Y., Bu, J., and Gu, X. (2022). Targeting ferroptosis, the achilles\u2019 heel of breast cancer: A review. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1036140"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lee, J.Y., Kim, W.K., Bae, K.H., Lee, S.C., and Lee, E.W. (2021). Lipid Metabolism and Ferroptosis. Biology, 10.","DOI":"10.3390\/biology10030184"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.2147\/OTT.S249752","article-title":"Identification of Pannexin 2 as a Novel Marker Correlating with Ferroptosis and Malignant Phenotypes of Prostate Cancer Cells","volume":"13","author":"Liao","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.molcel.2013.08.003","article-title":"Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy","volume":"51","author":"Ichimura","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"eade9585","DOI":"10.1126\/sciadv.ade9585","article-title":"NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8","volume":"9","author":"Anandhan","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40478-015-0225-z","article-title":"Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase","volume":"3","author":"Malik","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.cmet.2012.10.001","article-title":"mTOR regulates cellular iron homeostasis through tristetraprolin","volume":"16","author":"Bayeva","year":"2012","journal-title":"Cell Metab."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Champion, J.D., Dodd, K.M., Lam, H.C., Alzahrani, M.A.M., Seifan, S., Rad, E., Scourfield, D.O., Fishel, M.L., Calver, B.L., and Ager, A. (2022). Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells. Cancers, 14.","DOI":"10.3390\/cancers14246195"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"36","DOI":"10.2174\/1874467211205010036","article-title":"APE1\/Ref-1 role in redox signaling: Translational applications of targeting the redox function of the DNA repair\/redox protein APE1\/Ref-1","volume":"5","author":"Kelley","year":"2012","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.cmet.2016.07.015","article-title":"Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis","volume":"24","author":"Xue","year":"2016","journal-title":"Cell Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41419-019-1528-y","article-title":"Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130\/STAT3 signaling pathway","volume":"10","author":"Kuang","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_59","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_60","doi-asserted-by":"crossref","first-page":"28","DOI":"10.4161\/cc.7.1.5145","article-title":"Role of the hypoxia inducible factors HIF in iron metabolism","volume":"7","author":"Peyssonnaux","year":"2008","journal-title":"Cell Cycle"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Xue, D., Zhou, X., and Qiu, J. (2020). Emerging role of NRF2 in ROS-mediated tumor chemoresistance. Biomed. Pharmacother., 131.","DOI":"10.1016\/j.biopha.2020.110676"},{"key":"ref_62","first-page":"413","article-title":"The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo","volume":"25","author":"Fujimori","year":"2004","journal-title":"Int. J. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/s41419-023-06070-x","article-title":"FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner","volume":"14","author":"Kim","year":"2023","journal-title":"Cell Death Dis."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/16\/2714\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:24Z","timestamp":1760034744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/16\/2714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":63,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cancers17162714"],"URL":"https:\/\/doi.org\/10.3390\/cancers17162714","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}