{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:19:16Z","timestamp":1788927556313,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7222164"],"award-info":[{"award-number":["7222164"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62076254"],"award-info":[{"award-number":["62076254"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ferroptosis is an iron-dependent form of regulated cell death that plays a critical role in tumor suppression and therapeutic response. However, the metabolic mechanisms that drive ferroptosis resistance in lung adenocarcinoma (LUAD), particularly in the context of EGFR-TKI tolerance, remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated transcriptomic and clinical data from TCGA LUAD cohort and performed survival and enrichment analyses. Functional assays, including proliferation, invasion, ferroptosis indicators, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      xenograft models, were used to evaluate the role of SLC16A3. Lactate rescue, transcription factor prediction (JASPAR), mIHC, and luciferase reporter assays were used to dissect regulatory mechanisms. Pharmacological inhibition of SLC16A3 was used to assess its therapeutic potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SLC16A3 expression was elevated in LUAD and was correlated with poor prognosis. SLC16A3 knockdown suppressed tumor cell growth and enhanced ferroptosis, as indicated by increased lipid peroxidation, iron accumulation, and mitochondrial depolarization. Lactate supplementation partially reversed ferroptosis induction. Mechanistically, SLC16A3 was transcriptionally activated by HIF1A, and the HIF1A-SLC16A3 axis conferred ferroptosis resistance and gefitinib tolerance. SLC16A3 inhibition restored ferroptotic sensitivity and enhanced EGFR-TKI efficacy in xenograft models\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings reveal that the HIF1A-SLC16A3-lactate axis orchestrates ferroptosis suppression and therapeutic resistance in LUAD. Targeting SLC16A3 represents a promising metabolic strategy for overcoming EGFR-TKI resistance by reactivating ferroptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1699540","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T05:18:23Z","timestamp":1762751903000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["SLC16A3 drives lung adenocarcinoma progression and gefitinib resistance through coordinated regulation of ferroptosis and lactate metabolism"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenhan","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zirui","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"B1","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":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810699","article-title":"Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma","volume":"361","author":"Mok","year":"2009","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70184-X","article-title":"Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study","volume":"12","author":"Zhou","year":"2011","journal-title":"Lancet Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3390\/biomedicines10020277","article-title":"Identification of targetable liabilities in the dynamic metabolic profile of EGFR-mutant lung adenocarcinoma: thinking beyond genomics for overcoming EGFR TKI resistance","volume":"10","author":"Gkountakos","year":"2022","journal-title":"Biomedicines"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1192","article-title":"Hypoxia induces resistance to EGFR inhibitors in lung cancer cells via upregulation of FGFR1 and the MAPK pathway","volume":"80","author":"Lu","year":"2020","journal-title":"Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41392-024-02082-x","article-title":"Lactate and lactylation in cancer","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B7","doi-asserted-by":"publisher","first-page":"107451","DOI":"10.1016\/j.pharmthera.2019.107451","article-title":"Lactate\/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon","volume":"206","author":"Brown","year":"2020","journal-title":"Pharmacol Ther"},{"key":"B8","doi-asserted-by":"publisher","first-page":"102647","DOI":"10.1016\/j.redox.2023.102647","article-title":"Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC\/MCT1 axis in lung cancer","volume":"61","author":"Liu","year":"2023","journal-title":"Redox Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2273008","DOI":"10.1080\/19336950.2023.2273008","article-title":"A systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventions","volume":"17","author":"Chatterjee","year":"2023","journal-title":"Channels (Austin)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/cai2.32","article-title":"Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma","volume":"1","author":"Zhu","year":"2022","journal-title":"Cancer Innov"},{"key":"B11","doi-asserted-by":"publisher","first-page":"150709","DOI":"10.1016\/j.bbrc.2024.150709","article-title":"Knockdown of SLC16A3 decreases extracellular lactate concentration in hepatocellular carcinoma, alleviates hypoxia and induces ferroptosis","volume":"733","author":"Shen","year":"2024","journal-title":"Biochem Biophys Res Commun"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0149-1","article-title":"Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion","volume":"19","author":"Friedmann Angeli","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s10565-025-10025-7","article-title":"Lipotoxicity, lipid peroxidation and ferroptosis: a dilemma in cancer therapy","volume":"41","author":"Ma","year":"2025","journal-title":"Cell Biol Toxicol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1372215","article-title":"SLC7A11 inhibits ferroptosis and downregulates PD-L1 levels in lung adenocarcinoma","volume":"15","author":"Huang","year":"2024","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.587436","article-title":"Comprehensive analysis of ferroptosis regulators in lung adenocarcinomas identifies prognostic and immunotherapy-related biomarkers","volume":"8","author":"Sun","year":"2021","journal-title":"Front Mol Biosci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"14614","DOI":"10.3390\/ijms241914614","article-title":"Regulation of ferroptosis in lung adenocarcinoma","volume":"24","author":"Wei","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"103553","DOI":"10.1016\/j.redox.2025.103553","article-title":"Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation","volume":"81","author":"Huang","year":"2025","journal-title":"Redox Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2024.01.041","article-title":"Zinc deficiency drives ferroptosis resistance by lactate production in esophageal squamous cell carcinoma","volume":"213","author":"Yang","year":"2024","journal-title":"Free Radic Biol Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13045-019-0720-y","article-title":"Ferroptosis, a new form of cell death: opportunities and challenges in cancer","volume":"12","author":"Mou","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/cac2.12250","article-title":"Ferroptosis in cancer and cancer immunotherapy","volume":"42","author":"Zhao","year":"2022","journal-title":"Cancer Commun (Lond)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.7150\/thno.55482","article-title":"Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma","volume":"11","author":"Zhang","year":"2021","journal-title":"Theranostics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/s41419-024-06914-0","article-title":"BUB1b impairs chemotherapy sensitivity via resistance to ferroptosis in lung adenocarcinoma","volume":"15","author":"Ding","year":"2024","journal-title":"Cell Death Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/s42003-023-04959-z","article-title":"KLF11 regulates lung adenocarcinoma ferroptosis and chemosensitivity by suppressing GPX4","volume":"6","author":"Zhao","year":"2023","journal-title":"Commun Biol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.c.7906502","article-title":"SCD1 inhibition blocks the AKT-NRF2-SLC7A11 pathway to induce lipid metabolism remodeling and ferroptosis priming in lung adenocarcinoma","volume":"85","author":"Sen","year":"2025","journal-title":"Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1007\/s00432-024-05752-z","article-title":"Knockdown of NADK promotes LUAD ferroptosis via NADPH\/FSP1 axis","volume":"150","author":"Meng","year":"2024","journal-title":"J Cancer Res Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.009093","article-title":"Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments","volume":"294","author":"Contreras-Baeza","year":"2019","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-023-03382-x","article-title":"Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer","volume":"72","author":"Wang","year":"2023","journal-title":"Cancer Immunol Immunother"},{"key":"B28","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/s12935-025-03791-1","article-title":"Comprehensive pan-cancer analysis identified SLC16A3 as a potential prognostic and diagnostic biomarker","volume":"25","author":"Yang","year":"2025","journal-title":"Cancer Cell Int"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.07.003","article-title":"The ubiquitin-proteasome system links NADPH metabolism to ferroptosis","volume":"33","author":"Yang","year":"2023","journal-title":"Trends Cell Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nature24637","article-title":"NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis","volume":"551","author":"Alvarez","year":"2017","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1021\/acscentsci.9b01063","article-title":"GTP cyclohydrolase 1\/tetrahydrobiopterin counteract ferroptosis through lipid remodeling","volume":"6","author":"Kraft","year":"2020","journal-title":"ACS Cent Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.chom.2025.02.003","article-title":"Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps","volume":"33","author":"Wise","year":"2025","journal-title":"Cell Host Microbe"},{"key":"B33","doi-asserted-by":"publisher","first-page":"123538","DOI":"10.1016\/j.biomaterials.2025.123538","article-title":"Lactate metabolism regulating nanosystem synergizes cuproptosis and ferroptosis to enhance cancer immunotherapy","volume":"325","author":"Zhi","year":"2026","journal-title":"Biomaterials"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-025-01587-4","article-title":"AARS1-mediated lactylation of H3K18 and STAT1 promotes ferroptosis in diabetic nephropathy","author":"Hong","year":"2025","journal-title":"Cell Death Differ"},{"key":"B35","doi-asserted-by":"publisher","first-page":"167447","DOI":"10.1016\/j.bbadis.2024.167447","article-title":"Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer","volume":"1870","author":"Zhang","year":"2024","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00448","article-title":"Discovery of 5-2-[5-chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl-4-methoxypyridine-2-carboxylic acid, a highly selective in vivo useable chemical probe to dissect MCT4 biology","volume":"64","author":"Heinrich","year":"2021","journal-title":"J Med Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00681-25","article-title":"Lactate metabolism is exploited by Francisella tularensis via its O-antigen capsule to limit macrophage-mediated activation and cell death","volume":"22","author":"Jessop","year":"2025","journal-title":"mBio"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70272","article-title":"Integrated single-cell and spatial transcriptome reveal metabolic gene SLC16A3 as a key regulator of immune suppression in hepatocellular carcinoma","volume":"28","author":"Kang","year":"2024","journal-title":"J Cell Mol Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1699540\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T05:18:23Z","timestamp":1762751903000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1699540\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2025.1699540"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1699540","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]},"article-number":"1699540"}}