{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:34:24Z","timestamp":1787027664237,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T00:00:00Z","timestamp":1715990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82273320"],"award-info":[{"award-number":["82273320"]}]},{"name":"National Natural Science Foundation of China","award":["82072999"],"award-info":[{"award-number":["82072999"]}]},{"name":"National Natural Science Foundation of China","award":["2019-I2 M-5-004"],"award-info":[{"award-number":["2019-I2 M-5-004"]}]},{"name":"National Natural Science Foundation of China","award":["2023NSFC0035"],"award-info":[{"award-number":["2023NSFC0035"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["82273320"],"award-info":[{"award-number":["82273320"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["82072999"],"award-info":[{"award-number":["82072999"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2019-I2 M-5-004"],"award-info":[{"award-number":["2019-I2 M-5-004"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2023NSFC0035"],"award-info":[{"award-number":["2023NSFC0035"]}]},{"name":"Province Natural Science Foundation of Sichuan","award":["82273320"],"award-info":[{"award-number":["82273320"]}]},{"name":"Province Natural Science Foundation of Sichuan","award":["82072999"],"award-info":[{"award-number":["82072999"]}]},{"name":"Province Natural Science Foundation of Sichuan","award":["2019-I2 M-5-004"],"award-info":[{"award-number":["2019-I2 M-5-004"]}]},{"name":"Province Natural Science Foundation of Sichuan","award":["2023NSFC0035"],"award-info":[{"award-number":["2023NSFC0035"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Oral squamous cell carcinoma (OSCC) stands as a prevalent subtype of head and neck squamous cell carcinoma, leading to disease recurrence and low survival rates. PPAR\u03b3, a ligand-dependent nuclear transcription factor, holds significance in tumor development. However, the role of PPAR\u03b3 in the development of OSCC has not been fully elucidated. Through transcriptome sequencing analysis, we discovered a notable enrichment of ferroptosis-related molecules upon treatment with PPAR\u03b3 antagonist. We subsequently confirmed the occurrence of ferroptosis through transmission electron microscopy, iron detection, etc. Notably, ferroptosis inhibitors could not completely rescue the cell death caused by PPAR\u03b3 inhibitors, and the rescue effect was the greatest when disulfidptosis and ferroptosis inhibitors coexisted. We confirmed that the disulfidptosis phenotype indeed existed. Mechanistically, through qPCR and Western blotting, we observed that the inhibition of PPAR\u03b3 resulted in the upregulation of heme oxygenase 1 (HMOX1), thereby promoting ferroptosis, while solute carrier family 7 member 11 (SLC7A11) was also upregulated to promote disulfidptosis in OSCC. Finally, a flow cytometry analysis of flight and multiplex immunohistochemical staining was used to characterize the immune status of PPAR\u03b3 antagonist-treated OSCC tissues in a mouse tongue orthotopic transplantation tumor model, and the results showed that the inhibition of PPAR\u03b3 led to ferroptosis and disulfidptosis, promoted the aggregation of cDCs and CD8+ T cells, and inhibited the progression of OSCC. Overall, our findings reveal that PPAR\u03b3 plays a key role in regulating cell death in OSCC and that targeting PPAR\u03b3 may be a potential therapeutic approach for OSCC.<\/jats:p>","DOI":"10.3390\/biom14050596","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T11:06:41Z","timestamp":1716203201000},"page":"596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["PPAR\u03b3 Antagonists Exhibit Antitumor Effects by Regulating Ferroptosis and Disulfidptosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Shiyu","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Gu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silu","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianming","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5173-0781","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1007\/s10495-022-01792-3","article-title":"Improved antitumor immunity of chemotherapy in OSCC treatment by Gasdermin-E mediated pyroptosis","volume":"28","author":"Zi","year":"2023","journal-title":"Apoptosis"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral squamous cell carcinomas: State of the field and emerging directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int. J. Oral. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nm.3159","article-title":"PPAR\u03b3 signaling and metabolism: The good, the bad and the future","volume":"19","author":"Ahmadian","year":"2013","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E68","DOI":"10.1152\/ajpendo.00367.2009","article-title":"Peroxisome proliferator-activated receptor-gamma regulates the expression and function of very-low-density lipoprotein receptor","volume":"298","author":"Tao","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1038\/s41467-023-38233-x","article-title":"PPAR-\u03b3 regulates the effector function of human T helper 9 cells by promoting glycolysis","volume":"14","author":"Bertschi","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e007031","DOI":"10.1136\/jitc-2023-007031","article-title":"PPAR\u03b3 activation modulates the balance of peritoneal macrophage populations to suppress ovarian tumor growth and tumor-induced immunosuppression","volume":"11","author":"Prat","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/s41420-022-01066-6","article-title":"CircRFWD3 promotes HNSCC metastasis by modulating miR-27a\/b\/PPAR\u03b3 signaling","volume":"8","author":"Wei","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"114100","DOI":"10.1016\/j.expneurol.2022.114100","article-title":"Peroxisome proliferator-activated receptor-\u03b3 ameliorates neuronal ferroptosis after traumatic brain injury in mice by inhibiting cyclooxygenase-2","volume":"354","author":"Liang","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.freeradbiomed.2022.06.247","article-title":"Loss of EMP1 promotes the metastasis of human bladder cancer cells by promoting migration and conferring resistance to ferroptosis through activation of PPAR gamma signaling","volume":"189","author":"Liu","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41580-023-00648-1","article-title":"Mechanisms controlling cellular and systemic iron homeostasis","volume":"5","author":"Galy","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41568-022-00459-0","article-title":"Targeting ferroptosis as a vulnerability in cancer","volume":"22","author":"Lei","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100985","DOI":"10.1016\/j.drup.2023.100985","article-title":"Inhibition of phosphoglycerate dehydrogenase induces ferroptosis and overcomes enzalutamide resistance in castration-resistant prostate cancer cells","volume":"70","author":"Wang","year":"2023","journal-title":"Drug Resist. Updat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41418-023-01239-5","article-title":"TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11\/xCT K11-linked ubiquitination and degradation","volume":"31","author":"Wang","year":"2024","journal-title":"Cell Death Differ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19721","DOI":"10.1074\/jbc.M117.814392","article-title":"Cystine uptake through the cystine\/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation","volume":"292","author":"Goji","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/s41556-020-0496-x","article-title":"Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer","volume":"22","author":"Liu","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41556-023-01091-2","article-title":"Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis","volume":"25","author":"Liu","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"155233","DOI":"10.1016\/j.metabol.2022.155233","article-title":"GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease","volume":"133","author":"Baumann","year":"2022","journal-title":"Metabolism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.phymed.2005.03.008","article-title":"In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARgamma in L6 myotubes","volume":"13","author":"Anandharajan","year":"2006","journal-title":"Phytomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.chom.2013.07.009","article-title":"PPAR\u03b3-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages","volume":"14","author":"Xavier","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.cmet.2017.03.011","article-title":"PPAR\u03b3 Links BMP2 and TGF\u03b21 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism","volume":"25","author":"Calvier","year":"2017","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5102","DOI":"10.1002\/anie.201310618","article-title":"Phenotypic screening to identify small-molecule enhancers for glucose uptake: Target identification and rational optimization of their efficacy","volume":"53","author":"Koh","year":"2014","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tang, Z., Ju, Y., Dai, X., Ni, N., Liu, Y., Zhang, D., Gao, H., Sun, H., Zhang, J., and Gu, P. (2021). HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration. Redox Biol., 43.","DOI":"10.1016\/j.redox.2021.101971"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1182\/blood.2020008455","article-title":"Excess heme upregulates heme oxygenase 1 and promotes cardiac ferroptosis in mice with sickle cell disease","volume":"139","author":"Menon","year":"2022","journal-title":"Blood"},{"key":"ref_25","first-page":"6","article-title":"Neutrophil ferroptosis causes immunosuppression","volume":"23","author":"Flemming","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.cmet.2021.02.015","article-title":"CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability","volume":"33","author":"Ma","year":"2021","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1002\/ptr.3442","article-title":"Upregulation of PPAR\u03b3 by Aegle marmelos ameliorates insulin resistance and \u03b2-cell dysfunction in high fat diet fed-streptozotocin induced type 2 diabetic rats","volume":"25","author":"Sharma","year":"2011","journal-title":"Phytother. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tcm.2005.04.002","article-title":"PPARgamma: A critical determinant of body fat distribution in humans and mice","volume":"15","author":"Tsai","year":"2005","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4687","DOI":"10.1038\/s41467-018-07133-w","article-title":"A structural mechanism for directing corepressor-selective inverse agonism of PPAR\u03b3","volume":"9","author":"Brust","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5825","DOI":"10.1038\/s41467-019-13768-0","article-title":"Definition of functionally and structurally distinct repressive states in the nuclear receptor PPAR\u03b3","volume":"10","author":"Heidari","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1111\/j.1349-7006.2006.00250.x","article-title":"Inhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties","volume":"97","author":"Takahashi","year":"2006","journal-title":"Cancer Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13287-023-03416-2","article-title":"PPAR\u03b3-dependent hepatic macrophage switching acts as a central hub for hUCMSC-mediated alleviation of decompensated liver cirrhosis in rats","volume":"14","author":"Yao","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1111\/j.1349-7006.2008.00904.x","article-title":"Inhibition of peroxisome proliferator-activated receptor gamma activity suppresses pancreatic cancer cell motility","volume":"99","author":"Nakajima","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2022.04.014","article-title":"Hydrogen sulfide alleviates particulate matter-induced emphysema and airway inflammation by suppressing ferroptosis","volume":"186","author":"Wang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, Z., Gan, S., Fu, L., Xu, Y., Wang, S., Zhang, G., Pan, D., Tao, L., and Shen, X. (2023). 1,8-Cineole ameliorates diabetic retinopathy by inhibiting retinal pigment epithelium ferroptosis via PPAR-\u03b3\/TXNIP pathways. Biomed. Pharmacother., 164.","DOI":"10.1016\/j.biopha.2023.114978"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/cac2.12487","article-title":"The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment: Molecular mechanisms and therapeutic controversy","volume":"43","author":"Zheng","year":"2023","journal-title":"Cancer Commun."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Huang, J., Zhang, J., Zhang, F., Lu, S., Guo, S., Shi, R., Zhai, Y., Gao, Y., Tao, X., and Jin, Z. (2023). Identification of a disulfidptosis-related genes signature for prognostic implication in lung adenocarcinoma. Comput. Biol. Med., 165.","DOI":"10.1016\/j.compbiomed.2023.107402"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dong, X., Liao, P., Liu, X., Yang, Z., Wang, Y., Zhong, W., and Wang, B. (2023). Construction and Validation of a Reliable Disulfidptosis-Related LncRNAs Signature of the Subtype, Prognostic, and Immune Landscape in Colon Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612915"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/5\/596\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:44:24Z","timestamp":1760107464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/5\/596"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,18]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["biom14050596"],"URL":"https:\/\/doi.org\/10.3390\/biom14050596","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,18]]}}}