{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:19:55Z","timestamp":1787062795502,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T00:00:00Z","timestamp":1765584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K10482"],"award-info":[{"award-number":["25K10482"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K07162"],"award-info":[{"award-number":["22K07162"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03527"],"award-info":[{"award-number":["19H03527"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K02336"],"award-info":[{"award-number":["24K02336"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008886","name":"Princess Takamatsu Cancer Research Fund","doi-asserted-by":"publisher","award":["22-25417"],"award-info":[{"award-number":["22-25417"]}],"id":[{"id":"10.13039\/501100008886","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Mesothelioma Treatment Advancement Fund","award":["2025M05"],"award-info":[{"award-number":["2025M05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Mesothelioma is a highly aggressive tumor with a poor prognosis that typically develops after a long latency period following asbestos exposure. Although immunotherapy combined with chemotherapy is increasingly used, the efficacy of standard treatments remains limited. This study aimed to explore ferroptosis induction as a potential therapeutic strategy for mesothelioma. Methods: We first screened microbial culture extracts collected from soil and marine environments to identify compounds with selective cytotoxicity against mesothelioma cells. Gene expression profiling was performed to investigate the mechanism of cell death induced by the identified compound. To assess intrinsic ferroptosis susceptibility, patient-derived mesothelioma cell lines and immortalized mesothelial cell lines were treated with RSL3, a GPX4 inhibitor. Results: Screening identified brefeldin A as a compound that selectively induces cell death in mesothelioma cells. Gene expression profiling revealed transcriptional changes consistent with ferroptosis induction. Treatment with RSL3 demonstrated marked variability in ferroptosis sensitivity across cell lines; the subgroup showing high sensitivity to RSL3 did not exhibit significant genetic alterations in NF2 or BAP1, but contained a significantly higher proportion of epithelioid tumors in histological classification. Conclusions: Our findings highlight ferroptosis induction as a promising antitumor mechanism in mesothelioma, particularly in the epithelioid subtype. While GPX4 inhibitors such as RSL3 are effective in vitro, further studies are needed to overcome pharmacological limitations and define molecular determinants of ferroptosis susceptibility, which may inform future personalized therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cancers17243983","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:32:37Z","timestamp":1765805557000},"page":"3983","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Epithelioid Mesothelioma Cells Exhibit Increased Ferroptosis Sensitivity Compared to Non-Epithelioid Mesothelioma Cells"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0689-1794","authenticated-orcid":false,"given":"Tatsuhiro","family":"Sato","sequence":"first","affiliation":[{"name":"Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikue","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruna","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3609-0717","authenticated-orcid":false,"given":"Taichi","family":"Ohshiro","sequence":"additional","affiliation":[{"name":"Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Minato-ku 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Minato-ku 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Kondo-Ida","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satomi","family":"Mukai","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Ohte","sequence":"additional","affiliation":[{"name":"Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Minato-ku 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Minato-ku 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Maeda","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan"},{"name":"College of Pharmacy, Kinjo Gakuin University, Nagoya 463-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Sekido","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan"},{"name":"Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e001717","DOI":"10.1136\/bmjph-2024-001717","article-title":"Global mortality burden of lung cancer and mesothelioma attributable to occupational asbestos exposure and the impact of national asbestos ban policies: A population-based study, 1990\u20132021","volume":"3","author":"Li","year":"2025","journal-title":"BMJ Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cardillo, G., Waller, D., Tenconi, S., Di Noia, V., and Ricciardi, S. (2025). Malignant Pleural Mesothelioma: A 2025 Update. J. Clin. Med., 14.","DOI":"10.3390\/jcm14031004"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41572-025-00640-3","article-title":"Pleural mesothelioma","volume":"11","author":"Fennell","year":"2025","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/his.15106","article-title":"Mesothelioma in the pleura, pericardium and peritoneum: Recommendations from the International Collaboration on Cancer Reporting (ICCR)","volume":"84","author":"Klebe","year":"2024","journal-title":"Histopathology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sekido, Y., and Sato, T. (2023). NF2 alteration in mesothelioma. Front. Toxicol., 5.","DOI":"10.3389\/ftox.2023.1161995"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1002\/1878-0261.12651","article-title":"Genetic alterations of malignant pleural mesothelioma: Association with tumor heterogeneity and overall survival","volume":"14","author":"Quetel","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cedres, S., Valdivia, A., Iranzo, P., Callejo, A., Pardo, N., Navarro, A., Martinez-Marti, A., Assaf-Pastrana, J.D., Felip, E., and Garrido, P. (2023). Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy. Cancers, 15.","DOI":"10.3390\/cancers15245787"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e038892","DOI":"10.1136\/bmjopen-2020-038892","article-title":"Mesothelioma and Radical Surgery 2 (MARS 2): Protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma","volume":"10","author":"Lim","year":"2020","journal-title":"BMJ Open"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jtho.2024.12.014","article-title":"A Perspective on the MARS2 Trial","volume":"20","author":"Lim","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.22.02542","article-title":"Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma","volume":"41","author":"Vogelzang","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label, phase 3 trial","volume":"397","author":"Baas","year":"2021","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/S1470-2045(20)30462-9","article-title":"Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): A multicentre, single-arm, phase 2 trial with a safety run-in","volume":"21","author":"Nowak","year":"2020","journal-title":"Lancet. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bertuccio, F.R., Montini, S., Fusco, M.A., Di Gennaro, A., Sciandrone, G., Agustoni, F., Galli, G., Bortolotto, C., Saddi, J., and Baietto, G. (2025). Malignant Pleural Mesothelioma: From Pathophysiology to Innovative Actionable Targets. Cancers, 17.","DOI":"10.3390\/cancers17071160"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Suraya, R., Nagano, T., and Tachihara, M. (2025). Recent Advances in Mesothelioma Treatment: Immunotherapy, Advanced Cell Therapy, and Other Innovative Therapeutic Modalities. Cancers, 17.","DOI":"10.3390\/cancers17040694"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zafar, A., Rashid, A.A., Moeed, A., Tahir, M.J., Khan, A.J., Shrateh, O.N., and Ahmed, A. (2024). Safety and efficacy of PD-1\/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: A systematic review and meta-analysis. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-13127-3"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"237ra68","DOI":"10.1126\/scitranslmed.3008639","article-title":"Merlin deficiency predicts FAK inhibitor sensitivity: A synthetic lethal relationship","volume":"6","author":"Shapiro","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5522","DOI":"10.1038\/onc.2017.147","article-title":"E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells","volume":"36","author":"Kato","year":"2017","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1038\/s41591-025-04029-3","article-title":"YAP\/TEAD inhibitor VT3989 in solid tumors: A phase 1\/2 trial","volume":"31","author":"Yap","year":"2025","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1158\/1535-7163.MCT-24-0308","article-title":"TEAD-Independent Cell Growth of Hippo-Inactive Mesothelioma Cells: Unveiling Resistance to TEAD Inhibitor K-975 through MYC Signaling Activation","volume":"24","author":"Akao","year":"2025","journal-title":"Mol. Cancer Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3670","DOI":"10.1016\/j.bbagen.2013.02.008","article-title":"Natural products: A continuing source of novel drug leads","volume":"1830","author":"Cragg","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Choi, Y., Kim, Y., Boo, H.J., Yoon, D., Cha, J.S., and Yoo, J. (2025). Natural Product-Derived Drugs: Structural Insights into Their Biological Mechanisms. Biomolecules, 15.","DOI":"10.3390\/biom15091303"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/1811072a0","article-title":"Decumbin, a new compound from a species of Penicillium","volume":"181","author":"Singleton","year":"1958","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13586","DOI":"10.1002\/cam4.6056","article-title":"Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations","volume":"12","author":"Sato","year":"2023","journal-title":"Cancer Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18545","DOI":"10.1016\/S0021-9258(19)81393-5","article-title":"Brefeldin A causes disassembly of the Golgi complex and accumulation of secretory proteins in the endoplasmic reticulum","volume":"263","author":"Fujiwara","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/0092-8674(89)90685-5","article-title":"Rapid redistribution of Golgi proteins into the ER in cells treated with brefeldin A: Evidence for membrane cycling from Golgi to ER","volume":"56","author":"Yuan","year":"1989","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41580-024-00794-0","article-title":"Homeostasis control in health and disease by the unfolded protein response","volume":"26","author":"Harnoss","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The Unfolded Protein Response and Cell Fate Control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.tcb.2023.05.003","article-title":"Regulation of ferroptosis by lipid metabolism","volume":"33","author":"Pope","year":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s42003-018-0212-6","article-title":"Golgi stress mediates redox imbalance and ferroptosis in human cells","volume":"1","author":"Alborzinia","year":"2018","journal-title":"Commun. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41586-019-1426-6","article-title":"Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling","volume":"572","author":"Wu","year":"2019","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s41556-018-0178-0","article-title":"BAP1 links metabolic regulation of ferroptosis to tumour suppression","volume":"20","author":"Zhang","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/s41419-021-03998-w","article-title":"Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines","volume":"12","author":"Zheng","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s10787-024-01439-6","article-title":"Sulfasalazine promotes ferroptosis through AKT-ERK1\/2 and P53-SLC7A11 in rheumatoid arthritis","volume":"32","author":"Zhao","year":"2024","journal-title":"Inflammopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Setayeshpour, Y., Lee, Y., and Chi, J.T. (2023). Environmental Determinants of Ferroptosis in Cancer. Cancers, 15.","DOI":"10.3390\/cancers15153861"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1083\/jcb.201701136","article-title":"The \u03b16\u03b24 integrin promotes resistance to ferroptosis","volume":"216","author":"Brown","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/s41598-022-04973-x","article-title":"A panel of emerging EMT genes identified in malignant mesothelioma","volume":"12","author":"Wu","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1537427","DOI":"10.1080\/2162402X.2018.1537427","article-title":"Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth","volume":"8","author":"Pappas","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41420-024-01825-7","article-title":"Ferroptosis: Emerging mechanisms, biological function, and therapeutic potential in cancer and inflammation","volume":"10","author":"Jin","year":"2024","journal-title":"Cell Death Discov."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/24\/3983\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T05:17:41Z","timestamp":1766035061000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/24\/3983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,13]]},"references-count":44,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cancers17243983"],"URL":"https:\/\/doi.org\/10.3390\/cancers17243983","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,13]]}}}