{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T14:42:07Z","timestamp":1793889727959,"version":"4.8.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"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>\n                    The transcription factor AP-2\u03b1 plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2\u03b1 in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2\u03b1 regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN\/CCl\n                    <jats:sub>4<\/jats:sub>\n                    -induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2a\n                    <jats:sup>\u0394Hep<\/jats:sup>\n                    and Tfap2a\n                    <jats:sup>\u0394M\u03a6<\/jats:sup>\n                    mice, but not in Tfap2a\n                    <jats:sup>\u0394HSC<\/jats:sup>\n                    mice fed with normal chow. Tfap2a\n                    <jats:sup>\u0394Hep<\/jats:sup>\n                    and Tfap2a\n                    <jats:sup>\u0394M\u03a6<\/jats:sup>\n                    mice treated with DEN\/CCl\n                    <jats:sub>4<\/jats:sub>\n                    for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2\u03b1 binds to the promoter regions of SREBP1\/ACC\/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2\u03b1 in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2\u03b1 expression and decreases lipid accumulation in HCC cells. Clinically, AP-2\u03b1 expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These results suggest that AP-2\u03b1 has been identified as a novel therapeutic target in fibrosis and inflammation-related HCC, exerting anti-lipogenesis, anti-inflammatory, and anti-tumor multi-roles.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07500-8","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T19:26:48Z","timestamp":1743794808000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Deletion of Tfap2a in hepatocytes and macrophages promotes the progression of hepatocellular carcinoma by regulating SREBP1\/FASN\/ACC pathway and anti-inflammatory effect of IL10"],"prefix":"10.1038","volume":"16","author":[{"given":"Zhiwei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guixiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiran","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyi","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7319-6441","authenticated-orcid":false,"given":"Xiaofeng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"7500_CR1","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMra1713263","volume":"380","author":"A Villanueva","year":"2019","unstructured":"Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380:1450\u201362.","journal-title":"N Engl J Med"},{"key":"7500_CR2","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41575-019-0186-y","volume":"16","author":"J Yang","year":"2019","unstructured":"Yang J, Hainaut P, Gores G, Amadou A, Plymoth A, Roberts L. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589\u2013604.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"7500_CR3","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3350\/cmh.2022.0402","volume":"29","author":"D Xie","year":"2023","unstructured":"Xie D, Shi J, Zhou J, Fan J, Gao Q. Clinical practice guidelines and real-life practice in hepatocellular carcinoma: a Chinese perspective. Clin Mol Hepatol. 2023;29:206\u201316.","journal-title":"Clin Mol Hepatol"},{"key":"7500_CR4","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1016\/j.cell.2019.10.038","volume":"179","author":"Q Gao","year":"2019","unstructured":"Gao Q, Zhu H, Dong L, Shi W, Chen R, Song Z, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell. 2019;179:1240.","journal-title":"Cell"},{"key":"7500_CR5","doi-asserted-by":"publisher","first-page":"512","DOI":"10.3390\/cells8050512","volume":"8","author":"N Berndt","year":"2019","unstructured":"Berndt N, Eckstein J, Heucke N, Gajowski R, Stockmann M, Meierhofer D, et al. Characterization of lipid and lipid droplet metabolism in human HCC. Cells. 2019;8:512.","journal-title":"Cells"},{"key":"7500_CR6","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1053\/j.gastro.2013.01.054","volume":"144","author":"A Budhu","year":"2013","unstructured":"Budhu A, Roessler S, Zhao X, Yu Z, Forgues M, Ji J, et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology. 2013;144:1066\u201375.e1061.","journal-title":"Gastroenterology"},{"key":"7500_CR7","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.biochi.2004.09.018","volume":"86","author":"D Eberl\u00e9","year":"2004","unstructured":"Eberl\u00e9 D, Hegarty B, Bossard P, Ferr\u00e9 P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004;86:839\u201348.","journal-title":"Biochimie"},{"key":"7500_CR8","doi-asserted-by":"publisher","first-page":"S138","DOI":"10.1194\/jlr.R800079-JLR200","volume":"50","author":"S Wakil","year":"2009","unstructured":"Wakil S, Abu-Elheiga L. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009;50:S138\u2013143.","journal-title":"J Lipid Res"},{"key":"7500_CR9","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nm.3159","volume":"19","author":"M Ahmadian","year":"2013","unstructured":"Ahmadian M, Suh JM, Hah N, Liddle C, Atkins A, Downes M. PPAR\u03b3 signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19:557\u201366.","journal-title":"Nat Med"},{"key":"7500_CR10","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/nrc.2016.89","volume":"16","author":"F R\u00f6hrig","year":"2016","unstructured":"R\u00f6hrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16:732\u201349.","journal-title":"Nat Rev Cancer"},{"key":"7500_CR11","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.tibs.2018.01.005","volume":"43","author":"R DeBose-Boyd","year":"2018","unstructured":"DeBose-Boyd R, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond. Trends Biochem Sci. 2018;43:358\u201368.","journal-title":"Trends Biochem Sci"},{"key":"7500_CR12","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1038\/nrc2222","volume":"7","author":"J Menendez","year":"2007","unstructured":"Menendez J, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763\u201377.","journal-title":"Nat Rev Cancer"},{"key":"7500_CR13","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","volume":"15","author":"I Dagogo-Jack","year":"2018","unstructured":"Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15:81\u201394.","journal-title":"Nat Rev Clin Oncol"},{"key":"7500_CR14","doi-asserted-by":"publisher","first-page":"e135197","DOI":"10.1172\/JCI135197","volume":"131","author":"J Hou","year":"2021","unstructured":"Hou J, Zhang J, Cui P, Zhou Y, Liu C, Wu X, et al. TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis. J Clin Invest. 2021;131:e135197.","journal-title":"J Clin Invest"},{"key":"7500_CR15","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s13046-016-0412-1","volume":"35","author":"L Kong","year":"2016","unstructured":"Kong L, Zhou Y, Bu H, Lv T, Shi Y, Yang J. Deletion of interleukin-6 in monocytes\/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J Exp Clin Cancer Res. 2016;35:131.","journal-title":"J Exp Clin Cancer Res"},{"key":"7500_CR16","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1038\/s41417-022-00432-x","volume":"29","author":"C Hu","year":"2022","unstructured":"Hu C, Li X, Sui Y, Chen Y, Zhao Y, Yang Y, et al. Dicer deletion in hepatocytes promotes macrophages M1 polarization through dysregulated miR-192-3p\/IGF2 in non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Gene Ther. 2022;29:1252\u201362.","journal-title":"Cancer Gene Ther"},{"key":"7500_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06888-z","volume":"15","author":"D Li","year":"2024","unstructured":"Li D, Zhang T, Guo Y, Bi C, Liu M, Wang G. Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma. Cell Death Dis. 2024;15:498.","journal-title":"Cell Death Dis"},{"key":"7500_CR18","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.jhep.2014.10.029","volume":"62","author":"O Yeung","year":"2015","unstructured":"Yeung O, Lo C, Ling C, Qi X, Geng W, Li C, et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol. 2015;62:607\u201316.","journal-title":"J Hepatol"},{"key":"7500_CR19","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.3892\/ijo.2016.3318","volume":"48","author":"W Huang","year":"2016","unstructured":"Huang W, Chen C, Liang Z, Qiu J, Li X, Hu X, et al. AP-2\u03b1 inhibits hepatocellular carcinoma cell growth and migration. Int J Oncol. 2016;48:1125\u201334.","journal-title":"Int J Oncol"},{"key":"7500_CR20","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.7150\/thno.33800","volume":"9","author":"W Huang","year":"2019","unstructured":"Huang W, Zhong Z, Luo C, Xiao Y, Li L, Zhang X, et al. The miR-26a\/AP-2\u03b1\/Nanog signaling axis mediates stem cell self-renewal and temozolomide resistance in glioma. Theranostics. 2019;9:5497\u2013516.","journal-title":"Theranostics"},{"key":"7500_CR21","doi-asserted-by":"publisher","first-page":"e29043","DOI":"10.1371\/journal.pone.0029043","volume":"6","author":"Y Wu","year":"2011","unstructured":"Wu Y, Xiao Y, Ding X, Zhuo Y, Ren P, Zhou C, et al. A miR-200b\/200c\/429-binding site polymorphism in the 3\u2019 untranslated region of the AP-2\u03b1 gene is associated with cisplatin resistance. PLoS One. 2011;6:e29043.","journal-title":"PLoS One"},{"key":"7500_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05878-x","volume":"14","author":"S Long","year":"2023","unstructured":"Long S, Huang G, Ouyang M, Xiao K, Zhou H, Hou A, et al. Epigenetically modified AP-2\u03b1 by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression. Cell Death Dis. 2023;14:365.","journal-title":"Cell Death Dis"},{"key":"7500_CR23","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1042\/BJ20091112","volume":"425","author":"V Payne","year":"2009","unstructured":"Payne V, Au W, Lowe C, Rahman S, Friedman J, O\u2019Rahilly S, et al. C\/EBP transcription factors regulate SREBP1c gene expression during adipogenesis. Biochem J. 2009;425:215\u201323.","journal-title":"Biochem J"},{"key":"7500_CR24","doi-asserted-by":"publisher","first-page":"3467","DOI":"10.1073\/pnas.95.7.3467","volume":"95","author":"M Jiang","year":"1998","unstructured":"Jiang M, Tang Q, McLenithan J, Geiman D, Shillinglaw W, Henzel W, et al. Derepression of the C\/EBPalpha gene during adipogenesis: identification of AP-2alpha as a repressor. Proc Natl Acad Sci USA. 1998;95:3467\u201371.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7500_CR25","doi-asserted-by":"publisher","first-page":"e36330","DOI":"10.7554\/eLife.36330","volume":"7","author":"C Scott","year":"2018","unstructured":"Scott C, Vossio S, Rougemont J, Gruenberg J. TFAP2 transcription factors are regulators of lipid droplet biogenesis. Elife. 2018;7:e36330.","journal-title":"Elife"},{"key":"7500_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25967-9","volume":"12","author":"C Liu","year":"2021","unstructured":"Liu C, Yang Y, Chen C, Li L, Li J, Wang X, et al. Environmental eustress modulates \u03b2-ARs\/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice. Nat Commun. 2021;12:5725.","journal-title":"Nat Commun"},{"key":"7500_CR27","doi-asserted-by":"publisher","first-page":"100086","DOI":"10.1016\/j.xpro.2020.100086","volume":"1","author":"M Charni-Natan","year":"2020","unstructured":"Charni-Natan M, Goldstein I. Protocol for primary mouse hepatocyte isolation. STAR Protoc. 2020;1:100086.","journal-title":"STAR Protoc"},{"key":"7500_CR28","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.jhep.2019.03.014","volume":"71","author":"X Zhang","year":"2019","unstructured":"Zhang X, Fan L, Wu J, Xu H, Leung W, Fu K, et al. Macrophage p38\u03b1 promotes nutritional steatohepatitis through M1 polarization. J Hepatol. 2019;71:163\u201374.","journal-title":"J Hepatol"},{"key":"7500_CR29","doi-asserted-by":"publisher","first-page":"2200742","DOI":"10.1002\/advs.202200742","volume":"9","author":"H Lin","year":"2022","unstructured":"Lin H, Wang L, Liu Z, Long K, Kong M, Ye D, et al. Hepatic MDM2 causes metabolic associated fatty liver disease by blocking triglyceride-VLDL secretion via ApoB degradation. Adv Sci. 2022;9:2200742.","journal-title":"Adv Sci"},{"key":"7500_CR30","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1038\/s41418-024-01365-8","volume":"31","author":"J Zhang","year":"2024","unstructured":"Zhang J, Chen P, Li X, Li L, Wu Q, Wang G, et al. Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease. Cell Death Differ. 2024;31:1636\u201349.","journal-title":"Cell Death Differ"},{"key":"7500_CR31","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1530\/JOE-16-0229","volume":"231","author":"X Ding","year":"2016","unstructured":"Ding X, Luo Y, Zhang X, Zheng H, Yang X, Yang X, et al. IL-33-driven ILC2\/eosinophil axis in fat is induced by sympathetic tone and suppressed by obesity. J Endocrinol. 2016;231:35\u201348.","journal-title":"J Endocrinol"},{"key":"7500_CR32","doi-asserted-by":"publisher","first-page":"138787","DOI":"10.1016\/j.chemosphere.2023.138787","volume":"331","author":"D Li","year":"2023","unstructured":"Li D, Miao J, Pan L, Zhou Y, Gao Z, Bi Y, et al. Integrated lipidomics and transcriptomics analysis reveal lipid metabolism disturbance in scallop (Chlamys farreri) exposure to benzo[a]pyrene. Chemosphere. 2023;331:138787.","journal-title":"Chemosphere"},{"key":"7500_CR33","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/nprot.2012.148","volume":"8","author":"D Dominissini","year":"2013","unstructured":"Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G. Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc. 2013;8:176\u201389.","journal-title":"Nat Protoc"},{"key":"7500_CR34","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/978-1-4939-6380-5_7","volume":"1480","author":"M Gagliardi","year":"2016","unstructured":"Gagliardi M, Matarazzo M. RIP: RNA Immunoprecipitation. Methods Mol Biol. 2016;1480:73\u201386.","journal-title":"Methods Mol Biol"},{"key":"7500_CR35","doi-asserted-by":"publisher","first-page":"e211","DOI":"10.1002\/cpz1.211","volume":"1","author":"T Uehara","year":"2021","unstructured":"Uehara T, Pogribny I, Rusyn I. The DEN and CCl(4)-induced mouse model of fibrosis and inflammation-associated hepatocellular carcinoma. Curr Protoc. 2021;1:e211.","journal-title":"Curr Protoc"},{"key":"7500_CR36","doi-asserted-by":"publisher","first-page":"7450","DOI":"10.7150\/thno.75936","volume":"12","author":"T Chen","year":"2022","unstructured":"Chen T, Yuan Z, Lei Z, Duan J, Xue J, Lu T, et al. Hippocalcin-Like 1 blunts liver lipid metabolism to suppress tumorigenesis via directly targeting RUVBL1-mTOR signaling. Theranostics. 2022;12:7450\u201364.","journal-title":"Theranostics"},{"key":"7500_CR37","doi-asserted-by":"publisher","first-page":"101529","DOI":"10.1016\/j.molmet.2022.101529","volume":"63","author":"C Zhang","year":"2022","unstructured":"Zhang C, Zhu N, Li H, Gong Y, Gu J, Shi Y, et al. New dawn for cancer cell death: Emerging role of lipid metabolism. Mol Metab. 2022;63:101529.","journal-title":"Mol Metab"},{"key":"7500_CR38","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.cmet.2015.09.028","volume":"22","author":"V Singh","year":"2015","unstructured":"Singh V, Chassaing B, Zhang L, San Yeoh B, Xiao X, Kumar M, et al. Microbiota-dependent hepatic lipogenesis mediated by stearoyl CoA desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell Metab. 2015;22:983\u201396.","journal-title":"Cell Metab"},{"key":"7500_CR39","first-page":"9702","volume":"10","author":"J Hu","year":"2020","unstructured":"Hu J, Wang H, Li X, Liu Y, Mi Y, Kong H, et al. Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder. Theranostics. 2020;10:9702\u201320.","journal-title":"T"},{"key":"7500_CR40","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1053\/gast.1997.v112.pm9041256","volume":"112","author":"H Louis","year":"1997","unstructured":"Louis H, Le Moine O, Peny M, Gulbis B, Nisol F, Goldman M, et al. Hepatoprotective role of interleukin 10 in galactosamine\/lipopolysaccharide mouse liver injury. Gastroenterology. 1997;112:935\u201342.","journal-title":"Gastroenterology"},{"key":"7500_CR41","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1002\/hep.26607","volume":"59","author":"J Wan","year":"2014","unstructured":"Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2014;59:130\u201342.","journal-title":"Hepatology"},{"key":"7500_CR42","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.celrep.2017.06.017","volume":"20","author":"Y Han","year":"2017","unstructured":"Han Y, Kim H, Na H, Nam M, Kim J, Kim J, et al. RORalpha induces KLF4-mediated M2 polarization in the liver macrophages that protect against nonalcoholic steatohepatitis. Cell Rep. 2017;20:124\u201335.","journal-title":"Cell Rep"},{"key":"7500_CR43","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/nature09968","volume":"473","author":"S Fu","year":"2011","unstructured":"Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 2011;473:528\u201331.","journal-title":"Nature"},{"key":"7500_CR44","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1172\/JCI0215593","volume":"109","author":"J Horton","year":"2002","unstructured":"Horton J, Goldstein J, Brown M. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125\u201331.","journal-title":"J Clin Invest"},{"key":"7500_CR45","doi-asserted-by":"publisher","first-page":"2308","DOI":"10.1242\/jcs.026062","volume":"121","author":"D Cunha","year":"2008","unstructured":"Cunha D, Hekerman P, Ladri\u00e8re L, Bazarra-Castro A, Ortis F, Wakeham M, et al. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci. 2008;121:2308\u201318.","journal-title":"J Cell Sci"},{"key":"7500_CR46","doi-asserted-by":"publisher","first-page":"2760","DOI":"10.1093\/nar\/27.13.2760","volume":"27","author":"N Mohibullah","year":"1999","unstructured":"Mohibullah N, Donner A, Ippolito J, Williams T. SELEX and missing phosphate contact analyses reveal flexibility within the AP-2[alpha] protein: DNA binding complex. Nucleic Acids Res. 1999;27:2760\u20139.","journal-title":"Nucleic Acids Res"},{"key":"7500_CR47","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/s41571-023-00774-x","volume":"20","author":"X Deng","year":"2023","unstructured":"Deng X, Qing Y, Horne D, Huang H, Chen J. The roles and implications of RNA m(6)A modification in cancer. Nat Rev Clin Oncol. 2023;20:507\u201326.","journal-title":"Nat Rev Clin Oncol"},{"key":"7500_CR48","doi-asserted-by":"publisher","first-page":"11366","DOI":"10.1111\/jcmm.15738","volume":"24","author":"J Wei","year":"2020","unstructured":"Wei J, Yin Y, Zhou J, Chen H, Peng J, Yang J, et al. METTL3 potentiates resistance to cisplatin through m(6) A modification of TFAP2C in seminoma. J Cell Mol Med. 2020;24:11366\u201380.","journal-title":"J Cell Mol Med"},{"key":"7500_CR49","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1016\/j.cell.2012.05.003","volume":"149","author":"K Meyer","year":"2012","unstructured":"Meyer K, Saletore Y, Zumbo P, Elemento O, Mason C, Jaffrey S. Comprehensive analysis of mRNA methylation reveals enrichment in 3\u2019 UTRs and near stop codons. Cell. 2012;149:1635\u201346.","journal-title":"Cell"},{"key":"7500_CR50","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1101\/gad.262766.115","volume":"29","author":"Y Yue","year":"2015","unstructured":"Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29:1343\u201355.","journal-title":"Genes Dev"},{"key":"7500_CR51","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.molcel.2019.04.025","volume":"74","author":"H Shi","year":"2019","unstructured":"Shi H, Wei J, He C. Where, when, and how: context-dependent functions of rna methylation writers, readers, and erasers. Mol Cell. 2019;74:640\u201350.","journal-title":"Mol Cell"},{"key":"7500_CR52","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41556-018-0045-z","volume":"20","author":"H Huang","year":"2018","unstructured":"Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285\u201395.","journal-title":"Nat Cell Biol"},{"key":"7500_CR53","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"J Llovet","year":"2021","unstructured":"Llovet J, Kelley R, Villanueva A, Singal A, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.","journal-title":"Nat Rev Dis Primers"},{"key":"7500_CR54","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1016\/j.cmet.2024.08.010","volume":"36","author":"X Wei","year":"2024","unstructured":"Wei X, Wu D, Li J, Wu M, Li Q, Che Z, et al. Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages. Cell Metab. 2024;36:2281\u201397.e2287.","journal-title":"Cell Metab"},{"key":"7500_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/srep44612","volume":"7","author":"W Luo","year":"2017","unstructured":"Luo W, Xu Q, Wang Q, Wu H, Hua J. Effect of modulation of PPAR-\u03b3 activity on Kupffer cells M1\/M2 polarization in the development of non-alcoholic fatty liver disease. Sci Rep. 2017;7:44612.","journal-title":"Sci Rep"},{"key":"7500_CR56","doi-asserted-by":"publisher","first-page":"4553","DOI":"10.1210\/en.2006-0417","volume":"147","author":"M den Boer","year":"2006","unstructured":"den Boer M, Voshol P, Schroder-van der Elst J, Korsheninnikova E, Ouwens D, Kuipers F, et al. Endogenous interleukin-10 protects against hepatic steatosis but does not improve insulin sensitivity during high-fat feeding in mice. Endocrinology. 2006;147:4553\u20138.","journal-title":"Endocrinology"},{"key":"7500_CR57","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.jhep.2007.12.017","volume":"48","author":"D Cintra","year":"2008","unstructured":"Cintra D, Pauli J, Araujo E, Moraes J, de Souza C, Milanski M, et al. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol. 2008;48:628\u201337.","journal-title":"J Hepatol"},{"key":"7500_CR58","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1038\/nrendo.2017.91","volume":"13","author":"H Shimano","year":"2017","unstructured":"Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol. 2017;13:710\u201330.","journal-title":"Nat Rev Endocrinol"},{"key":"7500_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2537","volume":"4","author":"L Eissing","year":"2013","unstructured":"Eissing L, Scherer T, T\u00f6dter K, Knippschild U, Greve J, Buurman W, et al. De novo lipogenesis in human fat and liver is linked to ChREBP-\u03b2 and metabolic health. Nat Commun. 2013;4:1528.","journal-title":"Nat Commun"},{"key":"7500_CR60","first-page":"505","volume":"3","author":"C Dorn","year":"2010","unstructured":"Dorn C, Riener M, Kirovski G, Saugspier M, Steib K, Weiss TG E, et al. Expression of fatty acid synthase in nonalcoholic fatty liver disease. Int J Clin Exp Pathol. 2010;3:505\u201314.","journal-title":"Int J Clin Exp Pathol"},{"key":"7500_CR61","doi-asserted-by":"publisher","first-page":"2508","DOI":"10.1002\/hep.32045","volume":"74","author":"Y Hu","year":"2021","unstructured":"Hu Y, He W, Huang Y, Xiang H, Guo J, Che Y, et al. Fatty acid synthase-suppressor screening identifies sorting Nexin 8 as a therapeutic target for NAFLD. Hepatology. 2021;74:2508\u201325.","journal-title":"Hepatology"},{"key":"7500_CR62","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/hep.31000","volume":"72","author":"M Syed-Abdul","year":"2020","unstructured":"Syed-Abdul M, Parks E, Gaballah A, Bingham K, Hammoud G, Kemble G, et al. Fatty acid synthase inhibitor TVB-2640 reduces hepatic de Novo lipogenesis in males with metabolic abnormalities. Hepatology. 2020;72:103\u201318.","journal-title":"Hepatology"},{"key":"7500_CR63","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1111\/dom.14272","volume":"23","author":"C Beysen","year":"2021","unstructured":"Beysen C, Schroeder P, Wu E, Brevard J, Ribadeneira M, Lu W, et al. Inhibition of fatty acid synthase with FT-4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non-alcoholic fatty liver disease: results from two early-phase randomized trials. Diabetes Obes Metab. 2021;23:700\u201310.","journal-title":"Diabetes Obes Metab"},{"key":"7500_CR64","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.cmet.2005.04.002","volume":"1","author":"M Chakravarthy","year":"2005","unstructured":"Chakravarthy M, Pan Z, Zhu Y, Tordjman K, Schneider J, Coleman T, et al. \u201cNew\u201d hepatic fat activates PPAR\u03b1 to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 2005;1:309\u201322.","journal-title":"Cell Metab"},{"key":"7500_CR65","doi-asserted-by":"publisher","first-page":"100479","DOI":"10.1016\/j.jhepr.2022.100479","volume":"4","author":"B Paul","year":"2022","unstructured":"Paul B, Lewinska M, Andersen J. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep. 2022;4:100479.","journal-title":"JHEP Rep"},{"key":"7500_CR66","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.jhep.2015.10.004","volume":"64","author":"L Li","year":"2016","unstructured":"Li L, Pilo G, Li X, Cigliano A, Latte G, Che L, et al. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J Hepatol. 2016;64:333\u201341.","journal-title":"J Hepatol"},{"key":"7500_CR67","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1136\/gutjnl-2018-317581","volume":"69","author":"L Che","year":"2020","unstructured":"Che L, Chi W, Qiao Y, Zhang J, Song X, Liu Y, et al. Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut. 2020;69:177\u201386.","journal-title":"Gut"},{"key":"7500_CR68","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1111\/febs.15144","volume":"287","author":"Q Hu","year":"2020","unstructured":"Hu Q, Mao Y, Liu M, Luo R, Jiang R, Guo F. The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK. FEBS J. 2020;287:2348\u201366.","journal-title":"FEBS J"},{"key":"7500_CR69","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.cell.2018.08.020","volume":"175","author":"J Kim","year":"2018","unstructured":"Kim J, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, et al. ER Stress drives lipogenesis and steatohepatitis via Caspase-2 activation of S1P. Cell. 2018;175:133\u201345.e115.","journal-title":"Cell"},{"key":"7500_CR70","doi-asserted-by":"crossref","first-page":"40","DOI":"10.2174\/1566523221666210907162005","volume":"22","author":"J Chen","year":"2022","unstructured":"Chen J, Zhang Q, Liu T, Tang H. Roles of M(6)A regulators in hepatocellular carcinoma: promotion or suppression. Curr Gene Ther. 2022;22:40\u201350.","journal-title":"Curr Gene Ther"},{"key":"7500_CR71","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1053-8","volume":"18","author":"Y Chen","year":"2019","unstructured":"Chen Y, Peng C, Chen J, Chen D, Yang B, He B, et al. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer. 2019;18:127.","journal-title":"Mol Cancer"},{"key":"7500_CR72","doi-asserted-by":"publisher","first-page":"852000","DOI":"10.3389\/fonc.2022.852000","volume":"12","author":"L Liang","year":"2022","unstructured":"Liang L, Xu H, Dong Q, Qiu L, Lu L, Yang Q, et al. WTAP is correlated with unfavorable prognosis, tumor cell proliferation, and immune infiltration in hepatocellular carcinoma. Front Oncol. 2022;12:852000.","journal-title":"Front Oncol"},{"key":"7500_CR73","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1126\/science.aay6018","volume":"367","author":"J Liu","year":"2020","unstructured":"Liu J, Dou X, Chen C, Chen C, Liu C, Xu M, et al. N (6)-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science. 2020;367:580\u20136.","journal-title":"Science"},{"key":"7500_CR74","doi-asserted-by":"publisher","first-page":"e1007412","DOI":"10.1371\/journal.pgen.1007412","volume":"14","author":"S Kasowitz","year":"2018","unstructured":"Kasowitz S, Ma J, Anderson S, Leu N, Xu Y, Gregory B, et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet. 2018;14:e1007412.","journal-title":"PLoS Genet"},{"key":"7500_CR75","doi-asserted-by":"publisher","first-page":"e31311","DOI":"10.7554\/eLife.31311","volume":"6","author":"I Roundtree","year":"2017","unstructured":"Roundtree I, Luo G, Zhang Z, Wang X, Zhou T, Cui Y, et al. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife. 2017;6:e31311.","journal-title":"Elife"},{"key":"7500_CR76","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1093\/hmg\/ddh167","volume":"13","author":"I Rafalska","year":"2004","unstructured":"Rafalska I, Zhang Z, Benderska N, Wolff H, Hartmann A, Brack-Werner R, et al. The intranuclear localization and function of YT521-B is regulated by tyrosine phosphorylation. Hum Mol Genet. 2004;13:1535\u201349.","journal-title":"Hum Mol Genet"},{"key":"7500_CR77","doi-asserted-by":"publisher","first-page":"3354","DOI":"10.1016\/j.celrep.2017.11.092","volume":"21","author":"H Shima","year":"2017","unstructured":"Shima H, Matsumoto M, Ishigami Y, Ebina M, Muto A, Sato Y, et al. S-Adenosylmethionine synthesis is regulated by selective N(6)-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep. 2017;21:3354\u201363.","journal-title":"Cell Rep"},{"key":"7500_CR78","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03186-2","volume":"11","author":"Z Zhang","year":"2020","unstructured":"Zhang Z, Wang Q, Zhao X, Shao L, Liu G, Zheng X, et al. YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA. Cell Death Dis. 2020;11:977.","journal-title":"Cell Death Dis"},{"key":"7500_CR79","doi-asserted-by":"publisher","first-page":"e22595","DOI":"10.1016\/j.heliyon.2023.e22595","volume":"9","author":"R Zhang","year":"2023","unstructured":"Zhang R, Yang R, Huang Z, Xu X, Lv S, Guan X, et al. METTL3\/YTHDC1-mediated upregulation of LINC00294 promotes hepatocellular carcinoma progression. Heliyon. 2023;9:e22595.","journal-title":"Heliyon"},{"key":"7500_CR80","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.apsb.2021.09.019","volume":"12","author":"D Du","year":"2022","unstructured":"Du D, Liu C, Qin M, Zhang X, Xi T, Yuan S, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B. 2022;12:558\u201380.","journal-title":"Acta Pharm Sin B"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07500-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07500-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07500-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T16:09:22Z","timestamp":1743869362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07500-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,3]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7500"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07500-8","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,3]]},"assertion":[{"value":"12 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 March 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 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":"This study was approved by the ethical principles and guidelines for Experiments on Animals and HCC tissues of Hunan Normal University (2018-035). Informed consent was gotten from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"245"}}