{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T22:31:26Z","timestamp":1786487486510,"version":"build-2736575974"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Triosephosphate isomerase 1 (TPI1) is aberrantly overexpressed and exerts a critical oncogenic role in the development and progression of various human cancers by regulating multiple malignant biological phenotypes. However, the biological functions of TPI1 and the molecular mechanisms underlying its regulatory effect on ferroptosis sensitivity in head and neck squamous cell carcinoma (HNSCC) remain not fully elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      TPI1 expression was analyzed across 33 cancer types using The Cancer Genome Atlas pan-cancer dataset, and validated in 6 paired HNSCC tumor\/adjacent normal tissues via Western blotting and immunohistochemistry. Clinical correlations were assessed using the Wilcoxon rank-sum test, and prognostic value was evaluated by Kaplan-Meier analysis and multivariate Cox regression. A prognostic nomogram integrating TPI1 and clinical covariates was constructed and validated by calibration curves. Single-cell RNA-sequencing (3 independent cohorts: GSE103322, GSE150321, GSE172577) and spatial transcriptomics (4 patient samples) were employed to map TPI1 cellular distribution in the tumor microenvironment. Gain- and loss-of-function assays were performed in FaDu (overexpression) and TU177 (knockdown) cell lines using lentiviral vectors. Cell proliferation was measured by CCK-8 and colony formation assays; migration and invasion were evaluated by wound healing and Transwell assays. Ferroptosis sensitivity was assessed by RSL3 dose-response curves, malondialdehyde (MDA) assay, BODIPY 581\/591 C\n                      <jats:sup>11<\/jats:sup>\n                      lipid peroxidation staining, and intracellular Fe\n                      <jats:sup>2+<\/jats:sup>\n                      quantification.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TPI1 was significantly upregulated in HNSCC at both mRNA and protein levels, with an AUC of 0.914 for distinguishing tumor from normal tissues. High TPI1 expression correlated with male sex, high histologic grade, advanced pathologic stage, and T3-T4 stage, and independently predicted poor overall survival. The nomogram integrating TPI1, age, gender, stage, and grade showed robust prognostic performance with well-calibrated 1-, 3-, and 5-year survival predictions. Single-cell and spatial transcriptomics confirmed that TPI1 was predominantly and specifically expressed in malignant epithelial cells, with minimal expression in stromal and immune cells. Functionally, TPI1 overexpression significantly enhanced FaDu cell proliferation, migration, and invasion, while TPI1 knockdown markedly suppressed these phenotypes in TU177 cells. Mechanistically, TPI1 conferred ferroptosis resistance by attenuating RSL3-induced lipid peroxidation, reactive oxygen species accumulation, and intracellular Fe\n                      <jats:sup>2+<\/jats:sup>\n                      elevation; conversely, TPI1 silencing sensitized HNSCC cells to ferroptotic cell death.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies TPI1 as a key tumor-promoting factor and independent prognostic biomarker in HNSCC. TPI1 promotes malignant progression by enhancing ferroptosis resistance, providing a promising therapeutic target for overcoming ferroptosis evasion in HNSCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1889940","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T22:10:37Z","timestamp":1786486237000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TPI1 promotes malignant progression and ferroptosis resistance in head and neck squamous cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Rui","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, China"]},{"name":"Department of Otorhinolaryngology, The Third Affiliated Hospital of Anhui Medical University (The First People\u2019s Hospital of Hefei)","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, The Third Affiliated Hospital of Anhui Medical University (The First People\u2019s Hospital of Hefei)","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehai","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1101\/gr.6.4.314","article-title":"A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13","volume":"6","author":"Ansari-Lari","year":"1996","journal-title":"Genome Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxid. Med. Cell Longev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1158\/2159-8290.Cd-20-1808","article-title":"Therapeutic targeting of the tumor microenvironment","volume":"11","author":"Bejarano","year":"2021","journal-title":"Cancer Discov."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e6865","DOI":"10.1097\/md.0000000000006865","article-title":"Clinical significance and prognostic value of triosephosphate isomerase expression in gastric cancer","volume":"96","author":"Chen","year":"2017","journal-title":"Med. Baltim."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.molcel.2023.03.005","article-title":"Ferroptosis: a flexible constellation of related biochemical mechanisms","volume":"83","author":"Dixon","year":"2023","journal-title":"Mol. Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4028","DOI":"10.1038\/s41598-022-08051-0","article-title":"Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer","volume":"12","author":"Enr\u00edquez-Flores","year":"2022","journal-title":"Sci. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"eabo5987","DOI":"10.1126\/scitranslmed.abo5987","article-title":"Pharmacogenomic landscape of head and neck squamous cell carcinoma informs precision oncology therapy","volume":"14","author":"Gu","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"184","DOI":"10.2174\/1573408012666160906110330","article-title":"Characterization of a new allelic variant of triosephosphate isomerase from the LNCaP human prostate cancer cell line: enzyme inhibition and spectroscopic studies","volume":"13","author":"Guzm\u00e1n-Luna","year":"2015","journal-title":"Curr. Enzym Inhib."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1016\/j.bbrc.2016.11.156","article-title":"Triosephosphate isomerase 1 suppresses growth, migration and invasion of hepatocellular carcinoma cells","volume":"482","author":"Jiang","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/s12967-022-03370-2","article-title":"TPI1 activates the PI3K\/AKT\/mTOR signaling pathway to induce breast cancer progression by stabilizing CDCA5","volume":"20","author":"Jin","year":"2022","journal-title":"J. Transl. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B13","doi-asserted-by":"publisher","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":"B14","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1186\/s40001-023-01568-8","article-title":"Triosephosphate isomerase 1 May be a risk predictor in laryngeal squamous cell carcinoma: a multi-centered study integrating bulk RNA, single-cell RNA, and protein immunohistochemistry","volume":"28","author":"Li","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"373","DOI":"10.2147\/jhc.S453249","article-title":"Single-cell RNA sequencing revealed that the enrichment of TPI1(+) malignant hepatocytes Was linked to HCC metastasis and immunosuppressive microenvironment","volume":"11","author":"Liang","year":"2024","journal-title":"J. Hepatocell. Carcinoma"},{"key":"B16","doi-asserted-by":"publisher","first-page":"153099","DOI":"10.1016\/j.bbrc.2025.153099","article-title":"TPI1 promotes tumor progression and M2 macrophage polarization: integrated pan-cancer and lung adenocarcinoma insights","volume":"797","author":"Liu","year":"2026","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1200\/jco.20.00275","article-title":"Diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck: ASCO guideline","volume":"38","author":"Maghami","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"B18","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1016\/S0021-9258(19)83687-6","article-title":"Human triosephosphate isomerase cDNA and protein structure. Studies of triosephosphate isomerase deficiency in man","volume":"260","author":"Maquat","year":"1985","journal-title":"J. Biol. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1016\/j.cmet.2024.07.008","article-title":"Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis","volume":"36","author":"Mo","year":"2024","journal-title":"Cell Metab."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010449","article-title":"Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis","volume":"24","author":"Rochette","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"B22","doi-asserted-by":"publisher","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":"B23","doi-asserted-by":"publisher","first-page":"2168","DOI":"10.1002\/elps.200800675","article-title":"Detection of autoantibodies against cyclophilin A and triosephosphate isomerase in sera from breast cancer patients by proteomic analysis","volume":"30","author":"Tamesa","year":"2009","journal-title":"Electrophoresis"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3622","DOI":"10.1111\/cas.16302","article-title":"Identification of TPI1 as a potential therapeutic target in pancreatic cancer with dependency of TP53 mutation using multi-omics analysis","volume":"115","author":"Toyoda","year":"2024","journal-title":"Cancer Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s00432-008-0367-5","article-title":"Identification of triosephosphate isomerase as an anti-drug resistance agent in human gastric cancer cells using functional proteomic analysis","volume":"134","author":"Wang","year":"2008","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s11684-023-0992-z","article-title":"Zooming in and out of ferroptosis in human disease","volume":"17","author":"Wang","year":"","journal-title":"Front. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"100916","DOI":"10.1016\/j.drup.2022.100916","article-title":"Overcoming cancer chemotherapy resistance by the induction of ferroptosis","volume":"66","author":"Wang","year":"","journal-title":"Drug Resist Updat"},{"key":"B28","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13046-024-03039-2","article-title":"Augmented ERO1\u03b1 upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11","volume":"43","author":"Wang","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/s41419-025-08368-4","article-title":"TPI1 enhances gemcitabine resistance in bladder cancer by promoting autophagy through activating Beclin-1","volume":"16","author":"Wang","year":"","journal-title":"Cell Death Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"107695","DOI":"10.1016\/j.phrs.2025.107695","article-title":"TPI1 promotes p53 ubiquitination in bladder cancer by recruiting AKT to enhance MDM2 phosphorylation","volume":"215","author":"Wang","year":"","journal-title":"Pharmacol. Res."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13051225","article-title":"Inhibition of TPI1 sensitizes cisplatin-resistant oral cancer to ferroptosis","volume":"13","author":"Wang","year":"","journal-title":"Biomedicines"},{"key":"B32","doi-asserted-by":"publisher","first-page":"112110","DOI":"10.1016\/j.cbi.2026.112110","article-title":"Ferroptosis mediated by aggregation of triosephosphate isomerase 1 links cadmium exposure to pulmonary fibrosis","author":"Yin","year":"2026","journal-title":"Chem. Biol. Interact."},{"key":"B33","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41419-025-07985-3","article-title":"Transcriptional activation of PHKG2 by TP53 promotes ferroptosis through nuclear export of NRF2 in head and neck squamous cell carcinoma","volume":"16","author":"Yu","year":"2025","journal-title":"Cell Death Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s10863-023-09987-2","article-title":"NFE2L1 restrains ferroptosis by transcriptionally regulating HJURP and participates in the progress of oral squamous cell carcinoma","volume":"55","author":"Zhang","year":"2023","journal-title":"J. Bioenerg. Biomembr."},{"key":"B35","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1158\/0008-5472.Can-24-3866","article-title":"CRB2 activates an epigenetic axis to promote ferroptosis in head and neck squamous cell carcinoma","volume":"86","author":"Zhang","year":"2026","journal-title":"Cancer Res."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1889940\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T22:10:37Z","timestamp":1786486237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1889940\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":35,"alternative-id":["10.3389\/fgene.2026.1889940"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1889940","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"article-number":"1889940"}}