{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:06:12Z","timestamp":1790247972050,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","award":["25K02785"],"award-info":[{"award-number":["25K02785"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","award":["25K20160"],"award-info":[{"award-number":["25K20160"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","award":["25K12735"],"award-info":[{"award-number":["25K12735"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25K02785"],"award-info":[{"award-number":["25K02785"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]},{"award":["25K20160"],"award-info":[{"award-number":["25K20160"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]},{"award":["25K12735"],"award-info":[{"award-number":["25K12735"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Zinc homeostasis has emerged as an important regulator of cancer biology, yet the biological and clinical significance of zinc transporter-associated transcriptional programs in head and neck squamous cell carcinoma (HNSCC) remains poorly understood. This study aimed to identify zinc transporter-associated epithelial tumor cell states and evaluate their molecular and clinical significance. Methods: Single-cell RNA sequencing data from an HNSCC cohort were analyzed to identify epithelial tumor cell populations associated with zinc transporter expression and to characterize their molecular features. A ZIP-active transcriptional signature was subsequently applied to The Cancer Genome Atlas (TCGA)-HNSCC cohort to evaluate biological characteristics, immune features, survival outcomes, and the influence of NFE2L2\/KEAP1\/CUL3 mutation status. Results: A distinct epithelial tumor cell population characterized by coordinated upregulation of SLC39A3 and SLC39A4 was identified and designated the ZIP-active tumor cell state. This population showed NRF2-associated oxidative stress adaptation, glutathione metabolism, and ferroptosis suppression, together with increased NRF2 activity. In the TCGA-HNSCC cohort, a high ZIP-active score was associated with oxidative stress adaptation, reduced T-cell-related immune signatures, and poorer overall survival. NFE2L2\/KEAP1\/CUL3-mutant tumors showed higher ZIP-active and NRF2-related scores than wild-type tumors, while NRF2-related metabolic features remained associated with ZIP activity in both groups. Conclusions: The ZIP-active tumor cell state represents an NRF2-linked metabolic program associated with oxidative stress adaptation, immune alterations, and adverse prognosis in HNSCC. Its persistence across NFE2L2\/KEAP1\/CUL3 mutation groups suggests that ZIP activity reflects NRF2-related tumor biology beyond genomic alterations alone.<\/jats:p>","DOI":"10.3390\/cancers18193104","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:16:28Z","timestamp":1790244988000},"page":"3104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A ZIP-Active Tumor Cell State Defines an NRF2-Associated Ferroptosis-Resistant and Immune-Cold Transcriptional Program in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2465-3992","authenticated-orcid":false,"given":"Hideyuki","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Miho","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Kaoru","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Hiroyuki","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Hiroe","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Toshiyuki","family":"Matsuyama","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-0102","authenticated-orcid":false,"given":"Kazuaki","family":"Chikamatsu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00428-024-03987-2","article-title":"Massive Parallel Sequencing of Head and Neck Conventional Squamous Cell Carcinomas: A Comprehensive Review","volume":"485","author":"Nadal","year":"2024","journal-title":"Virchows. 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