{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T22:23:51Z","timestamp":1794522231905,"version":"4.9.1"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gastric cancer is the most common primary malignant tumor of the digestive system. Recent studies have shown that targeting tumor cell metabolic reprogramming is a key cancer treatment strategy. NLR family pyrin domain containing 12 (NLRP12) is related to innate immunity, inflammation and tumorigenesis, but its role in the progression of gastric cancer remains unclear. The present study revealed that NLRP12 was highly expressed in gastric cancer tissues and cells, as well as positively correlated with poor patient prognosis and survival. NLRP12 promoted the progression of gastric cancer mainly by promoting the metabolic reprogramming of gastric cancer cells, the expression of histone H3 lysine 18 lactylation (H3K18la) and the stabilization of hexokinase 2 (HK2), a crucial enzyme in glycolysis. In the present study, NLRP12 competes with HK2 for binding to TRIM25, selectively reducing the K63-linked ubiquitination of HK2. Moreover, NLRP12 also exerted a significant cancer-promoting effect in mouse models. In summary, the present study demonstrated that NLRP12 prevents TRIM25 from mediating the K63-linked ubiquitination of HK2, which inhibits HK2 degradation through the autophagosome-lysosome pathway, thereby increasing its protein stability. These changes increase lactic acid production and induce H3K18la, which increases Myc transcription, thereby advancing gastric cancer progression. These findings reveal a novel cancer-promoting mechanism of NLRP12, potentially leading to the identification of new therapeutic targets for gastric cancer treatment.<\/jats:p>","DOI":"10.1038\/s41419-025-07923-3","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:05:43Z","timestamp":1755043543000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["NLRP12 decreases TRIM25-mediated HK2 degradation to promote glycolysis and H3K18la in gastric cancer"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0305-5203","authenticated-orcid":false,"given":"Linsen","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haohai","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4156-0288","authenticated-orcid":false,"given":"Haofeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"7923_CR1","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.3748\/wjg.v29.i16.2452","volume":"29","author":"WJ Yang","year":"2023","unstructured":"Yang WJ, Zhao HP, Yu Y, Wang JH, Guo L, Liu JY, et al. Updates on global epidemiology, risk and prognostic factors of gastric cancer. World J Gastroenterol. 2023;29:2452\u201368.","journal-title":"World J Gastroenterol"},{"key":"7923_CR2","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/S0140-6736(20)31288-5","volume":"396","author":"EC Smyth","year":"2020","unstructured":"Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396:635\u201348.","journal-title":"Lancet"},{"key":"7923_CR3","doi-asserted-by":"crossref","unstructured":"Zhang X, Li Y, Chen Y. Development of a comprehensive gene signature linking hypoxia, glycolysis, lactylation, and metabolomic insights in gastric cancer through the integration of bulk and single-cell RNA-seq data. Biomedicines. 2023;11:2948.","DOI":"10.3390\/biomedicines11112948"},{"key":"7923_CR4","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1007\/s12094-023-03278-3","volume":"26","author":"J Liu","year":"2024","unstructured":"Liu J, Bai X, Zhang M, Wu S, Xiao J, Zeng X, et al. Energy metabolism: a new target for gastric cancer treatment. Clin Transl Oncol. 2024;26:338\u201351.","journal-title":"Clin Transl Oncol"},{"key":"7923_CR5","doi-asserted-by":"publisher","first-page":"1149989","DOI":"10.3389\/fimmu.2023.1149989","volume":"14","author":"H Yang","year":"2023","unstructured":"Yang H, Zou X, Yang S, Zhang A, Li N, et al. Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer. Front Immunol. 2023;14:1149989.","journal-title":"Front Immunol"},{"key":"7923_CR6","doi-asserted-by":"publisher","first-page":"104630","DOI":"10.1016\/j.isci.2022.104630","volume":"25","author":"D Yang","year":"2022","unstructured":"Yang D, Yin J, Shan L, Yi X, Zhang W, et al. Identification of lysine-lactylated substrates in gastric cancer cells. iScience. 2022;25:104630.","journal-title":"iScience"},{"key":"7923_CR7","doi-asserted-by":"publisher","first-page":"7285","DOI":"10.2174\/0929867326666181213092652","volume":"26","author":"SN Garcia","year":"2019","unstructured":"Garcia SN, Guedes RC, Marques MM. Unlocking the potential of HK2 in cancer metabolism and therapeutics. Curr Med Chem. 2019;26:7285\u2013322.","journal-title":"Curr Med Chem"},{"key":"7923_CR8","doi-asserted-by":"publisher","first-page":"111075","DOI":"10.1016\/j.biopha.2020.111075","volume":"133","author":"H Yu","year":"2021","unstructured":"Yu H, Zhao K, Zeng H, Li Z, Chen K, Zhang Z, et al. N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability. Biomed Pharmacother. 2021;133:111075.","journal-title":"Biomed Pharmacother"},{"key":"7923_CR9","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1016\/j.cmet.2023.06.013","volume":"35","author":"H Rho","year":"2023","unstructured":"Rho H, Terry AR, Chronis C, Hay N. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis. Cell Metab. 2023;35:1406\u201323.","journal-title":"Cell Metab"},{"key":"7923_CR10","doi-asserted-by":"publisher","first-page":"116120","DOI":"10.1016\/j.bcp.2024.116120","volume":"222","author":"Y Zhao","year":"2024","unstructured":"Zhao Y, Jiang J, Zhou P, Deng K, Liu Z, Yang M, et al. H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis. Biochem Pharm. 2024;222:116120.","journal-title":"Biochem Pharm"},{"key":"7923_CR11","doi-asserted-by":"publisher","first-page":"111462","DOI":"10.1016\/j.cellsig.2024.111462","volume":"124","author":"Z Li","year":"2024","unstructured":"Li Z, Liang P, Chen Z, Chen Z, Jin T, He F, et al. CAF-secreted LOX promotes PD-L1 expression via histone lactylation and regulates tumor EMT through TGF\u03b2\/IGF1 signaling in gastric cancer. Cell Signal. 2024;124:111462.","journal-title":"Cell Signal"},{"key":"7923_CR12","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1093\/ajcn\/nqz347","volume":"111","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Wang J, Wang X, Gao T, Tian H, Zhou D, et al. The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia. Am J Clin Nutr. 2020;111:570\u20139.","journal-title":"Am J Clin Nutr"},{"key":"7923_CR13","doi-asserted-by":"publisher","first-page":"116323","DOI":"10.1016\/j.biopha.2024.116323","volume":"173","author":"KQ Li","year":"2024","unstructured":"Li KQ, Bai X, Ke AT, Ding SQ, Zhang CD, et al. Ubiquitin-specific proteases: from biological functions to potential therapeutic applications in gastric cancer. Biomed Pharmacother. 2024;173:116323.","journal-title":"Biomed Pharmacother"},{"key":"7923_CR14","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.semcancer.2025.02.004","volume":"110","author":"D Yang","year":"2025","unstructured":"Yang D, Yang C, Huang L, Guan M, Song C. Role of ubiquitination-driven metabolisms in oncogenesis and cancer therapy. Semin Cancer Biol. 2025;110:17\u201335.","journal-title":"Semin Cancer Biol"},{"key":"7923_CR15","doi-asserted-by":"publisher","first-page":"188954","DOI":"10.1016\/j.bbcan.2023.188954","volume":"1878","author":"M Rahimi-Tesiye","year":"2023","unstructured":"Rahimi-Tesiye M, Zaersabet M, Salehiyeh S, Jafari SZ. The role of TRIM25 in the occurrence and development of cancers and inflammatory diseases. Biochim Biophys Acta Rev Cancer. 2023;1878:188954.","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"7923_CR16","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/s41467-019-14190-2","volume":"11","author":"Y Liu","year":"2020","unstructured":"Liu Y, Tao S, Liao L, Li Y, Li H, Li Z, et al. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting the Keap1-Nrf2 pathway. Nat Commun. 2020;11:348.","journal-title":"Nat Commun"},{"key":"7923_CR17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41392-024-01763-x","volume":"9","author":"Y Yan","year":"2024","unstructured":"Yan Y, Zhou S, Chen X, Yi Q, Feng S, Zhao Z, et al. Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis. Signal Transduct Target Ther. 2024;9:58.","journal-title":"Signal Transduct Target Ther"},{"key":"7923_CR18","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1111\/cas.15763","volume":"114","author":"X Zhao","year":"2023","unstructured":"Zhao X, Zhou T, Wang Y, Bao M, Ni C, Ding L, et al. Trigred motif 36 regulates neuroendocrine differentiation of prostate cancer via HK2 ubiquitination and GPx4 deficiency. Cancer Sci. 2023;114:2445\u201359.","journal-title":"Cancer Sci"},{"key":"7923_CR19","doi-asserted-by":"publisher","first-page":"100887","DOI":"10.1016\/j.mam.2020.100887","volume":"76","author":"S Tuladhar","year":"2020","unstructured":"Tuladhar S, Kanneganti TD. NLRP12 in innate immunity and inflammation. Mol Asp Med. 2020;76:100887.","journal-title":"Mol Asp Med"},{"key":"7923_CR20","doi-asserted-by":"publisher","first-page":"175995","DOI":"10.1016\/j.ejphar.2023.175995","volume":"956","author":"L Huang","year":"2023","unstructured":"Huang L, Tao Y, Wu X, Wu J, Shen M, et al. The role of NLRP12 in inflammatory diseases. Eur J Pharm. 2023;956:175995.","journal-title":"Eur J Pharm"},{"key":"7923_CR21","doi-asserted-by":"crossref","unstructured":"Khan S, Kwak YT, Peng L, Hu S, Cantarel BL, Lewis CM, et al. NLRP12 downregulates the Wnt\/beta-catenin pathway via interaction with STK38 to suppress colorectal cancer. J Clin Invest. 2023;133:e166295.","DOI":"10.1172\/JCI166295"},{"key":"7923_CR22","doi-asserted-by":"crossref","unstructured":"Khan S, Zaki H. Crosstalk between NLRP12 and JNK during hepatocellular carcinoma. Int J Mol Sci. 2020;21:496.","DOI":"10.3390\/ijms21020496"},{"key":"7923_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-04286-4","volume":"7","author":"D Karan","year":"2017","unstructured":"Karan D, Tawfik O, Dubey S. Expression analysis of inflammasome sensors and implication of NLRP12 inflammasome in prostate cancer. Sci Rep. 2017;7:4378.","journal-title":"Sci Rep"},{"key":"7923_CR24","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.chom.2019.02.013","volume":"25","author":"ST Chen","year":"2019","unstructured":"Chen ST, Chen L, Lin DS, Chen SY, Tsao YP, Guo H, et al. NLRP12 regulates anti-viral RIG-I activation via interaction with TRIM25. Cell Host Microbe. 2019;25:602\u201316.","journal-title":"Cell Host Microbe"},{"key":"7923_CR25","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1038\/s41418-024-01295-5","volume":"31","author":"D Wang","year":"2024","unstructured":"Wang D, Du G, Chen X, Wang J, Liu K, Zhao H, et al. Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer. Cell Death Differ. 2024;31:779\u201391.","journal-title":"Cell Death Differ"},{"key":"7923_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07603-2","volume":"16","author":"Q Yang","year":"2025","unstructured":"Yang Q, Shen X, Luo Y, Li R, Meng X, Xu P, et al. Elane enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease. Cell Death Dis. 2025;16:266.","journal-title":"Cell Death Dis"},{"key":"7923_CR27","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1097\/CJI.0000000000000528","volume":"47","author":"ZG Zhu","year":"2024","unstructured":"Zhu ZG, Wang Z, Wu Q, Miao DL, Jin YQ, et al. Identification of the CD8 + T-cell related signature for predicting the prognosis of gastric cancer based on integrated analysis of bulk and single-cell RNA sequencing data. J Immunother. 2024;47:239\u201348.","journal-title":"J Immunother"},{"key":"7923_CR28","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1016\/j.semcancer.2022.09.007","volume":"86","author":"S Paul","year":"2022","unstructured":"Paul S, Ghosh S, Kumar S. Tumor glycolysis, an essential sweet tooth of tumor cells. Semin Cancer Biol. 2022;86:1216\u201330.","journal-title":"Semin Cancer Biol"},{"key":"7923_CR29","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","volume":"574","author":"D Zhang","year":"2019","unstructured":"Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575\u201380.","journal-title":"Nature"},{"key":"7923_CR30","doi-asserted-by":"crossref","unstructured":"Anauate AC, Leal MF, Calcagno DQ, Gigek CO, Karia B, Wisnieski F, et al. The complex network between MYC oncogene and microRNAs in gastric cancer: an overview. Int J Mol Sci. 2020;21:1782.","DOI":"10.3390\/ijms21051782"},{"key":"7923_CR31","doi-asserted-by":"crossref","unstructured":"Ciscato F, Ferrone L, Masgras I, Laquatra C, Rasola A. Hexokinase 2 in cancer: a prima donna playing multiple characters. Int J Mol Sci. 2021;22:4716.","DOI":"10.3390\/ijms22094716"},{"key":"7923_CR32","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1080\/15548627.2017.1381804","volume":"14","author":"L Jiao","year":"2018","unstructured":"Jiao L, Zhang HL, Li DD, Yang KL, Tang J, Li X, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018;14:671\u201384.","journal-title":"Autophagy"},{"key":"7923_CR33","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1158\/2326-6066.CIR-16-0269","volume":"5","author":"R Karki","year":"2017","unstructured":"Karki R, Man SM, Kanneganti TD. Inflammasomes and cancer. Cancer Immunol Res. 2017;5:94\u20139.","journal-title":"Cancer Immunol Res"},{"key":"7923_CR34","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1007\/s00018-015-2123-8","volume":"73","author":"N Sharma","year":"2016","unstructured":"Sharma N, Jha S. NLR-regulated pathways in cancer: opportunities and obstacles for therapeutic interventions. Cell Mol Life Sci. 2016;73:1741\u201364.","journal-title":"Cell Mol Life Sci"},{"key":"7923_CR35","doi-asserted-by":"crossref","unstructured":"Faubert B, Solmonson A, Deberardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368:eaaw5473.","DOI":"10.1126\/science.aaw5473"},{"key":"7923_CR36","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.2147\/OTT.S189687","volume":"12","author":"Y Liu","year":"2019","unstructured":"Liu Y, Zhang Z, Wang J, Chen C, Tang X, Zhu J, et al. Metabolic reprogramming results in abnormal glycolysis in gastric cancer: a review. Onco Targets Ther. 2019;12:1195\u2013204.","journal-title":"Onco Targets Ther"},{"key":"7923_CR37","doi-asserted-by":"publisher","first-page":"e2300898","DOI":"10.1002\/advs.202300898","volume":"10","author":"Q Yang","year":"2023","unstructured":"Yang Q, Lei X, He J, Peng Y, Zhang Y, Ling R, et al. N4-acetylcytidine drives glycolysis addiction in gastric cancer via NAT10\/SEPT9\/HIF-1alpha positive feedback loop. Adv Sci. 2023;10:e2300898.","journal-title":"Adv Sci"},{"key":"7923_CR38","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1186\/s13046-023-02827-6","volume":"42","author":"C Zhang","year":"2023","unstructured":"Zhang C, Wang H, Liu Q, Dai S, Tian G, Wei X, et al. LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement. J Exp Clin Cancer Res. 2023;42:246.","journal-title":"J Exp Clin Cancer Res"},{"key":"7923_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-23598-8","volume":"12","author":"R Li","year":"2022","unstructured":"Li R, Mei S, Ding Q, Wang Q, Yu L, et al. A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors. Sci Rep. 2022;12:18807.","journal-title":"Sci Rep"},{"key":"7923_CR40","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-016-0280-y","volume":"16","author":"H Wang","year":"2016","unstructured":"Wang H, Wang L, Zhang Y, Wang J, Deng Y, et al. Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. Cancer Cell Int. 2016;16:9.","journal-title":"Cancer Cell Int"},{"key":"7923_CR41","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1007\/s00726-023-03287-0","volume":"55","author":"P Ramesh","year":"2023","unstructured":"Ramesh P, Behera SK, Kotimoole CN, Mohanty V, Raju R, Prasad T, et al. Mining proteomics data to extract post-translational modifications associated with gastric cancer. Amino Acids. 2023;55:993\u20131001.","journal-title":"Amino Acids"},{"key":"7923_CR42","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1083\/jcb.201503044","volume":"210","author":"HG Xia","year":"2015","unstructured":"Xia HG, Najafov A, Geng J, Galan-Acosta L, Han X, Guo Y, et al. Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death. J Cell Biol. 2015;210:705\u201316.","journal-title":"J Cell Biol"},{"key":"7923_CR43","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s13046-020-01617-8","volume":"39","author":"JJ Chen","year":"2020","unstructured":"Chen JJ, Ren YL, Shu CJ, Zhang Y, Chen MJ, Xu J, et al. JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25\/SP1\/MMP2 axis. J Exp Clin Cancer Res. 2020;39:118.","journal-title":"J Exp Clin Cancer Res"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07923-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07923-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07923-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T21:11:11Z","timestamp":1757452271000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07923-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7923"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07923-3","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]},"assertion":[{"value":"14 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The present study was approved by the Ethics Committee of Yancheng Clinical College of Xuzhou Medical University (2024-K(YJ)-183). The Animal Care Committee of Jiangsu Vocational College of Medicine approved all the animal experiments (Approval No. XMLL-2024-800). All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"615"}}