{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:56:37Z","timestamp":1781646997706,"version":"3.54.5"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Key project of Anhui University Scientific Research Program","award":["No.2024AH051969"],"award-info":[{"award-number":["No.2024AH051969"]}]},{"name":"Introduction of Talents Special Research Fund Project","award":["No.YR202427"],"award-info":[{"award-number":["No.YR202427"]}]},{"name":"Introduction of Talents Special Research Fund Project","award":["No.YR202407"],"award-info":[{"award-number":["No.YR202407"]}]},{"name":"Anhui Province clinical medical research transformation project","award":["No.202527c10020096"],"award-info":[{"award-number":["No.202527c10020096"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biol Direct"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ferroptosis is a novel regulatory mechanism of cell death caused by iron-dependent lipid peroxidation (lipid-ROS) accumulation. The aim of this study was to explore whether dihydrolipoic acid transacetylase (DLAT) influences ferroptosis to promote the progression of gastric cancer (GC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The expression of DLAT in GC tissues and cell lines was examined by qRT-PCR, western blotting, and immunohistochemistry. Kaplan\u2013Meier survival curve analysis was used to estimate overall survival, and the log-rank test was used to estimate recurrence-free survival. The functional role of DLAT in GC was evaluated using in vitro and in vivo experiments including MTT, scratch healing tests, transwell assays and a xenograft tumor mouse model. Ferroptosis was evaluated by using malondialdehyde (MDA), reduced glutathione (GSH), lactate dehydrogenase (LDH), and superoxide dismutase (SOD) detection kits, iron accumulation assays, lipid ROS quantification, and mitochondrial deep red fluorescence staining kits. Western blotting was used to detect the biomarkers of ferroptosis and the interactions between DLAT and Nrf2, HO-1 and GPX4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that DLAT was upregulated in GC cells and tissues, and high DLAT expression indicated poor prognosis. Knockdown of DLAT inhibited the proliferation, invasion and metastasis of GC cells by increasing the levels of MDA and LDH, promoting the accumulation of Fe\n                      <jats:sup>2+<\/jats:sup>\n                      and lipid ROS, consuming GSH and SOD, reducing mitochondrial membrane potential, and suppressing the expression of GPX4. Overexpression of GPX4 can specifically salvage the growth inhibition of GC cells caused by DLAT knockdown, but did not affect the activity of the upstream DLAT, Nrf2 and HO-1. The inhibition of ferroptosis by DLAT was related to the regulation of the Nrf2\/HO-1\/GPX4 antioxidant axis. In\n                      <jats:italic>vivo<\/jats:italic>\n                      , DLAT inhibited the Nrf2\/HO-1 axis, hindering the growth of transplanted tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These results indicated that DLAT deficiency increased accumulation of Fe\n                      <jats:sup>2+<\/jats:sup>\n                      and lipid ROS, enhanced disruption of mitochondrial membrane potential, and induced ferroptosis through the Nrf2\/HO-1\/GPX4 axis, thereby inhibiting the malignant progression of GC cells. DLAT serves as a prognostic biomarker and potential therapeutic target for GC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Registry and the Registration of the study\/trial: N\/A.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13062-026-00767-7","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:40:55Z","timestamp":1775122855000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DLAT inhibits ferroptosis to promote malignant progression of gastric cancer through Nrf2\/HO-1\/GPX4 signaling pathway"],"prefix":"10.1186","volume":"21","author":[{"given":"Lin","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengwei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"767_CR1","first-page":"394","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394\u2013424.","journal-title":"CA Cancer J Clin"},{"issue":"9","key":"767_CR2","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1007\/s11864-020-00774-4","volume":"21","author":"TH Patel","year":"2020","unstructured":"Patel TH, Cecchini M. Targeted therapies in advanced gastric cancer. Curr Treat Options Oncol. 2020;21(9):70.","journal-title":"Curr Treat Options Oncol"},{"issue":"6586","key":"767_CR3","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.abf0529","volume":"375","author":"P Tsvetkov","year":"2022","unstructured":"Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375(6586):1254\u201361.","journal-title":"Science"},{"issue":"10","key":"767_CR4","doi-asserted-by":"publisher","first-page":"4269","DOI":"10.18632\/aging.204728","volume":"15","author":"L Xu","year":"2023","unstructured":"Xu L, Wu P, Rong A, et al. Systematic pan-cancer analysis identifies cuproptosis-related gene DLAT as an immunological and prognostic biomarker. Aging (Albany NY). 2023;15(10):4269\u201387.","journal-title":"Aging"},{"issue":"6","key":"767_CR5","first-page":"1140","volume":"7","author":"WQ Goh","year":"2015","unstructured":"Goh WQ, Ow GS, Kuznetsov VA, Chong S, Lim YP. DLAT subunit of the pyruvate dehydrogenase complex is upregulated in gastric cancer-implications in cancer therapy. Am J Transl Res. 2015;7(6):1140\u201351.","journal-title":"Am J Transl Res"},{"issue":"5","key":"767_CR6","doi-asserted-by":"publisher","first-page":"e2006203","DOI":"10.1371\/journal.pbio.2006203","volume":"16","author":"H Feng","year":"2018","unstructured":"Feng H, Stockwell BR. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 2018;16(5):e2006203.","journal-title":"PLoS Biol"},{"key":"767_CR7","doi-asserted-by":"publisher","first-page":"865689","DOI":"10.3389\/fphar.2022.865689","volume":"13","author":"W Yang","year":"2022","unstructured":"Yang W, Wang Y, Zhang C, et al. Maresin1 protect against ferroptosis-induced liver injury through ROS inhibition and Nrf2\/HO-1\/GPX4 activation. Front Pharmacol. 2022;13:865689.","journal-title":"Front Pharmacol"},{"issue":"11","key":"767_CR8","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.7150\/ijbs.59404","volume":"17","author":"R Wei","year":"2021","unstructured":"Wei R, Zhao Y, Wang J, et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells. Int J Biol Sci. 2021;17(11):2703\u201317.","journal-title":"Int J Biol Sci"},{"key":"767_CR9","first-page":"350","volume":"20","author":"X Fang","year":"2020","unstructured":"Fang X, Cai Z, Wang H, Han D, Cheng Q, Zhang P, Gao F, Yu Y, Song Z, Wu Q, Jiang X. A novel role of Nrf2 in ferroptosis: regulation of ferroptosis-related genes. Nat Rev Cancer. 2020;20:350\u201364.","journal-title":"Nat Rev Cancer"},{"issue":"4","key":"767_CR10","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","volume":"22","author":"X Jiang","year":"2021","unstructured":"Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22(4):266\u201382.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"3","key":"767_CR11","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.tcb.2015.10.014","volume":"26","author":"WS Yang","year":"2016","unstructured":"Yang WS, Stockwell BR, Ferroptosis. Death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165\u201376.","journal-title":"Trends Cell Biol"},{"issue":"1","key":"767_CR12","doi-asserted-by":"publisher","first-page":"2503130","DOI":"10.1080\/13510002.2025.2503130","volume":"30","author":"L Zhang","year":"2025","unstructured":"Zhang L, Liu X, Wang J, et al. Kaempferol protects against doxorubicin-induced myocardial damage by inhibiting mitochondrial ROS-dependent ferroptosis. Redox Rep. 2025;30(1):2503130.","journal-title":"Redox Rep"},{"issue":"18","key":"767_CR13","doi-asserted-by":"publisher","first-page":"6469","DOI":"10.3390\/molecules28186469","volume":"28","author":"C Favaron","year":"2023","unstructured":"Favaron C, Gabano E, Zanellato I, Arrais A, Marzano C, Ravera M. Effects of ferrocene and ferrocenium on MCF-7 breast cancer cells and interconnection with regulated cell death pathways. Molecules. 2023;28(18):6469.","journal-title":"Molecules"},{"key":"767_CR14","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41586-020-2623-z","volume":"585","author":"JM Ubellacker","year":"2020","unstructured":"Ubellacker JM, Tasdogan A, Ramesh V, et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 2020;585:113\u20138.","journal-title":"Nature"},{"key":"767_CR15","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13058-019-1177-1","volume":"21","author":"A Nagpal","year":"2019","unstructured":"Nagpal A, Redvers RP, Ling X, et al. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+\u2009ve breast cancer metastasis. Breast Cancer Res. 2019;21:94.","journal-title":"Breast Cancer Res"},{"key":"767_CR16","doi-asserted-by":"publisher","first-page":"101060","DOI":"10.1016\/j.redox.2018.11.018","volume":"25","author":"SO Pohl","year":"2019","unstructured":"Pohl SO, Pervaiz S, Dharmarajan A, Agostino M. Gene expression analysis of heatshock proteins and redox regulators reveals combinatorial prognostic markers in carcinomas of the gastrointestinal tract. Redox Biol. 2019;25:101060.","journal-title":"Redox Biol"},{"key":"767_CR17","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/s41571-020-00462-0","volume":"18","author":"X Chen","year":"2021","unstructured":"Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18:280\u201396.","journal-title":"Nat Rev Clin Oncol"},{"key":"767_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2021.09.014","volume":"522","author":"Y Lu","year":"2021","unstructured":"Lu Y, Qin H, Jiang B, et al. KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma. Cancer Lett. 2021;522:1\u201313.","journal-title":"Cancer Lett"},{"issue":"4","key":"767_CR19","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1093\/humrep\/deaa363","volume":"36","author":"Y Li","year":"2021","unstructured":"Li Y, Zeng X, Lu D, Yin M, Shan M, Gao Y. Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis. Hum Reprod. 2021;36(4):951\u201364.","journal-title":"Hum Reprod"},{"key":"767_CR20","doi-asserted-by":"publisher","first-page":"155401","DOI":"10.1016\/j.phymed.2024.155401","volume":"128","author":"W Li","year":"2024","unstructured":"Li W, Yin X, Fu H, et al. Ethanol extract of Eclipta prostrata induces multiple myeloma ferroptosis via Keap1\/Nrf2\/HO-1 axis. Phytomedicine. 2024;128:155401.","journal-title":"Phytomedicine"},{"issue":"14","key":"767_CR21","doi-asserted-by":"publisher","first-page":"e70012","DOI":"10.1002\/cam4.70012","volume":"13","author":"Y Peng","year":"2024","unstructured":"Peng Y, Shi R, Yang S, Zhu J. Cuproptosis-related gene DLAT is a biomarker of the prognosis and immune microenvironment of gastric cancer and affects the invasion and migration of cells. Cancer Med. 2024;13(14):e70012.","journal-title":"Cancer Med"},{"issue":"6","key":"767_CR22","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/j.ccell.2019.04.002","volume":"35","author":"B Hassannia","year":"2019","unstructured":"Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting Ferroptosis to Iron Out Cancer. Cancer Cell. 2019;35(6):830\u201349.","journal-title":"Cancer Cell"},{"issue":"7679","key":"767_CR23","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/nature24297","volume":"551","author":"MJ Hangauer","year":"2017","unstructured":"Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551(7679):247\u201350.","journal-title":"Nature"},{"key":"767_CR24","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41586-020-2623-z","volume":"585","author":"JM Ubellacker","year":"2020","unstructured":"Ubellacker JM, Tasdogan A, Ramesh V, et al. Lymph protects metastasizing melanoma cells from ferroptosis[J]. Nature. 2020;585:113\u20138.","journal-title":"Nature"},{"issue":"7","key":"767_CR25","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41568-022-00459-0","volume":"22","author":"G Lei","year":"2022","unstructured":"Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381\u201396.","journal-title":"Nat Rev Cancer"},{"issue":"9","key":"767_CR26","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1080\/15548627.2020.1810918","volume":"17","author":"X Chen","year":"2021","unstructured":"Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy. 2021;17(9):2054\u201381.","journal-title":"Autophagy"},{"key":"767_CR27","doi-asserted-by":"publisher","first-page":"592413","DOI":"10.3389\/fonc.2020.592413","volume":"10","author":"Y Shan","year":"2020","unstructured":"Shan Y, Yang G, Huang H, et al. Ubiquitin-Like Modifier Activating Enzyme 1 as a Novel Diagnostic and Prognostic Indicator That Correlates With Ferroptosis and the Malignant Phenotypes of Liver Cancer Cells. Front Oncol. 2020;10:592413.","journal-title":"Front Oncol"},{"issue":"3","key":"767_CR28","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1158\/2159-8290.CD-21-0922","volume":"12","author":"R Pillai","year":"2022","unstructured":"Pillai R, Hayashi M, Zavitsanou AM, Papagiannakopoulos T. NRF2: KEAPing Tumors Protected. Cancer Discov. 2022;12(3):625\u201343.","journal-title":"Cancer Discov"},{"key":"767_CR29","doi-asserted-by":"publisher","first-page":"101107","DOI":"10.1016\/j.redox.2019.101107","volume":"23","author":"M Dodson","year":"2019","unstructured":"Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107.","journal-title":"Redox Biol"},{"issue":"11","key":"767_CR30","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1016\/j.jid.2019.03.1165","volume":"140","author":"W Fang","year":"2020","unstructured":"Fang W, Tang L, Wang G, et al. Molecular Hydrogen Protects Human Melanocytes from Oxidative Stress by Activating Nrf2 Signaling. J Invest Dermatol. 2020;140(11):2230\u2013e22419.","journal-title":"J Invest Dermatol"},{"key":"767_CR31","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41419-021-04348-6","volume":"13","author":"Z Song","year":"2022","unstructured":"Song Z, Xiang X, Li J, Zhu Y, Wang Z, Wang Y. Inhibition of Nrf2 enhances sensitivity of gastric cancer cells to ferroptosis. Cell Death Dis. 2022;13:48.","journal-title":"Cell Death Dis"},{"issue":"11","key":"767_CR32","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.1002\/mc.70037","volume":"64","author":"L Yang","year":"2025","unstructured":"Yang L, Li H, Yang Y, Dong L, Li Y, Lv Y. GDF15-Mediated Regulation of Ferroptosis: Unraveling the p62\/Keap1\/Nrf2 Pathway in Gastric Cancer Development. Mol Carcinog. 2025;64(11):1885\u201398.","journal-title":"Mol Carcinog"}],"container-title":["Biology Direct"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13062-026-00767-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13062-026-00767-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13062-026-00767-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:23:49Z","timestamp":1781645029000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13062-026-00767-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["767"],"URL":"https:\/\/doi.org\/10.1186\/s13062-026-00767-7","relation":{},"ISSN":["1745-6150"],"issn-type":[{"value":"1745-6150","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]},"assertion":[{"value":"23 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent was obtained from all participants. This study was in accordance with the Declaration of Helsinki Ethical Guidelines and was approved by the Institutional Ethical Review Committee of the First Affiliated Hospital of Wannan Medical College (2024-SR-75). The animal studies were performed in accordance with the animal experiment guidelines, and approved by the Animal Protection Committee of Wannan Medical College (WNMC-AWE-2024159).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"64"}}