{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T11:24:45Z","timestamp":1787397885844,"version":"build-2736575974"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"the Shenzhen Science and Technology Program","award":["JCYJ20230807094802006"],"award-info":[{"award-number":["JCYJ20230807094802006"]}]},{"name":"the Shenzhen Science and Technology Program","award":["JCYJ20240813152357075"],"award-info":[{"award-number":["JCYJ20240813152357075"]}]},{"DOI":"10.13039\/501100001809","name":"the Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374531"],"award-info":[{"award-number":["82374531"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82205209"],"award-info":[{"award-number":["82205209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Transl Oncol"],"DOI":"10.1007\/s12094-026-04302-y","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T19:09:39Z","timestamp":1773515379000},"page":"3973-3991","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FAT4 loss promotes tumor growth and ferroptosis resistance in hepatocellular carcinoma via PI3K\/AKT pathway activation"],"prefix":"10.1007","volume":"28","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kongli","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minling","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhou","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2153-8661","authenticated-orcid":false,"given":"Xinfeng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,14]]},"reference":[{"issue":"Suppl","key":"4302_CR1","doi-asserted-by":"publisher","first-page":"S228","DOI":"10.3350\/cmh.2024.0824","volume":"31","author":"SY Hwang","year":"2025","unstructured":"Hwang SY, Danpanichkul P, Agopian V, Mehta N, Parikh ND, Abou-Alfa GK, et al. Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol. 2025;31(Suppl):S228-s254.","journal-title":"Clin Mol Hepatol"},{"issue":"1","key":"4302_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02075-w","volume":"10","author":"J Zheng","year":"2025","unstructured":"Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther. 2025;10(1):35.","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"4302_CR3","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41392-025-02282-z","volume":"10","author":"S Pedretti","year":"2025","unstructured":"Pedretti S, Palermo F, Braghin M, Imperato G, Tomaiuolo P, Celikag M, et al. D-lactate and glycerol as potential biomarkers of sorafenib activity in hepatocellular carcinoma. Signal Transduct Target Ther. 2025;10(1):200.","journal-title":"Signal Transduct Target Ther"},{"issue":"8","key":"4302_CR4","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1038\/s43018-025-01037-7","volume":"6","author":"JM Ubellacker","year":"2025","unstructured":"Ubellacker JM, Dixon SJ. Prospects for ferroptosis therapies in cancer. Nat Cancer. 2025;6(8):1326\u201336.","journal-title":"Nat Cancer"},{"issue":"5","key":"4302_CR5","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1038\/s43018-025-00937-y","volume":"6","author":"L Zhou","year":"2025","unstructured":"Zhou L, Lian G, Zhou T, Cai Z, Yang S, Li W, et al. Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity. Nat Cancer. 2025;6(5):768\u201385.","journal-title":"Nat Cancer"},{"issue":"7755","key":"4302_CR6","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-019-1170-y","volume":"569","author":"W Wang","year":"2019","unstructured":"Wang W, Green M, Choi JE, Gij\u00f3n M, Kennedy PD, Johnson JK, et al. CD8(+) t cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569(7755):270\u20134.","journal-title":"Nature"},{"issue":"24","key":"4302_CR7","doi-asserted-by":"publisher","first-page":"6233","DOI":"10.1158\/0008-5472.CAN-21-1547","volume":"81","author":"F Fan","year":"2021","unstructured":"Fan F, Liu P, Bao R, Chen J, Zhou M, Mo Z, et al. A dual PI3K\/HDAC inhibitor induces immunogenic ferroptosis to potentiate cancer immune checkpoint therapy. Cancer Res. 2021;81(24):6233\u201345.","journal-title":"Cancer Res"},{"issue":"9","key":"4302_CR8","doi-asserted-by":"publisher","first-page":"3621","DOI":"10.7150\/ijbs.96014","volume":"20","author":"X Zhu","year":"2024","unstructured":"Zhu X, Sha X, Zang Y, Ren Q, Zhang S, Ma D, et al. Current progress of ferroptosis study in hepatocellular carcinoma. Int J Biol Sci. 2024;20(9):3621\u201337.","journal-title":"Int J Biol Sci"},{"issue":"5","key":"4302_CR9","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(5):280\u201396.","journal-title":"Nat Rev Clin Oncol"},{"key":"4302_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2025.101224","volume":"81","author":"Z Zhang","year":"2025","unstructured":"Zhang Z, Zhou Q, Li Z, Huang F, Mo K, Shen C, et al. DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal \u03b2-oxidation in hepatocellular carcinoma. Drug Resist Updat. 2025;81:101224.","journal-title":"Drug Resist Updat"},{"issue":"1\u20132","key":"4302_CR11","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","volume":"156","author":"WS Yang","year":"2014","unstructured":"Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1\u20132):317\u201331.","journal-title":"Cell"},{"issue":"1","key":"4302_CR12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1002\/med.21286","volume":"34","author":"E Sadeqzadeh","year":"2014","unstructured":"Sadeqzadeh E, de Bock CE, Thorne RF. Sleeping giants: emerging roles for the fat cadherins in health and disease. Med Res Rev. 2014;34(1):190\u2013221.","journal-title":"Med Res Rev"},{"issue":"1","key":"4302_CR13","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13046-019-1043-0","volume":"38","author":"R Wei","year":"2019","unstructured":"Wei R, Xiao Y, Song Y, Yuan H, Luo J, Xu W. FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis. J Exp Clin Cancer Res. 2019;38(1):112.","journal-title":"J Exp Clin Cancer Res"},{"issue":"1","key":"4302_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-023-02758-2","volume":"42","author":"D Wang","year":"2023","unstructured":"Wang D, Wu S, He J, Sun L, Zhu H, Zhang Y, et al. FAT4 overexpression promotes antitumor immunity by regulating the \u03b2-catenin\/STT3\/PD-L1 axis in cervical cancer. J Exp Clin Cancer Res. 2023;42(1):222.","journal-title":"J Exp Clin Cancer Res"},{"key":"4302_CR15","doi-asserted-by":"publisher","DOI":"10.1097\/HC9.0000000000000338","author":"FY Huang","year":"2023","unstructured":"Huang FY, Wong DK, Mak LY, Cheung TT, Zhang SS, Chau HT, et al. FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways. Hepatol Commun. 2023. https:\/\/doi.org\/10.1097\/HC9.0000000000000338.","journal-title":"Hepatol Commun"},{"issue":"1","key":"4302_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-42560-w","volume":"13","author":"J Li","year":"2023","unstructured":"Li J, Lv M, Huang Q, Hu R, Zhong X, Sun X, et al. FAT4 expression in peripheral blood mononuclear cells is associated with prognosis and immune cell infiltration in hepatocellular carcinoma. Sci Rep. 2023;13(1):15735.","journal-title":"Sci Rep"},{"key":"4302_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15082130","author":"J Bang","year":"2023","unstructured":"Bang J, Jun M, Lee S, Moon H, Ro SW. Targeting EGFR\/PI3K\/AKT\/mTOR signaling in hepatocellular carcinoma. Pharmaceutics. 2023. https:\/\/doi.org\/10.3390\/pharmaceutics15082130.","journal-title":"Pharmaceutics"},{"issue":"1","key":"4302_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07842-3","volume":"16","author":"R Ren","year":"2025","unstructured":"Ren R, Zhang S, Peng Z, Ji X, Song H, Wang Q, et al. Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K\/AKT pathway. Cell Death Dis. 2025;16(1):538.","journal-title":"Cell Death Dis"},{"key":"4302_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106553","volume":"187","author":"MDA Paskeh","year":"2023","unstructured":"Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, et al. Biological impact and therapeutic perspective of targeting PI3K\/Akt signaling in hepatocellular carcinoma: promises and challenges. Pharmacol Res. 2023;187:106553.","journal-title":"Pharmacol Res"},{"issue":"28","key":"4302_CR20","doi-asserted-by":"publisher","first-page":"4667","DOI":"10.3748\/wjg.v27.i28.4667","volume":"27","author":"T Liu","year":"2021","unstructured":"Liu T, Xie XL, Zhou X, Chen SX, Wang YJ, Shi LP, et al. Y-box binding protein 1 augments sorafenib resistance via the PI3K\/Akt signaling pathway in hepatocellular carcinoma. World J Gastroenterol. 2021;27(28):4667\u201386.","journal-title":"World J Gastroenterol"},{"issue":"1","key":"4302_CR21","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01355-2","volume":"21","author":"SH Seo","year":"2023","unstructured":"Seo SH, Cho KJ, Park HJ, Lee HW, Kim BK, Park JY, et al. Inhibition of Dickkopf-1 enhances the anti-tumor efficacy of sorafenib via inhibition of the PI3K\/Akt and Wnt\/\u03b2-catenin pathways in hepatocellular carcinoma. Cell Commun Signal. 2023;21(1):339.","journal-title":"Cell Commun Signal"},{"issue":"1","key":"4302_CR22","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02401-6","volume":"41","author":"B Liu","year":"2022","unstructured":"Liu B, Fang X, Kwong DL, Zhang Y, Verhoeft K, Gong L, et al. Targeting TROY-mediated P85a\/AKT\/TBX3 signaling attenuates tumor stemness and elevates treatment response in hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41(1):182.","journal-title":"J Exp Clin Cancer Res"},{"key":"4302_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2025.101246","volume":"81","author":"J Xu","year":"2025","unstructured":"Xu J, Wang B, Liu Q, Guo S, Chen C, Wu J, et al. MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance. Drug Resist Updat. 2025;81:101246.","journal-title":"Drug Resist Updat"},{"key":"4302_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101181","volume":"78","author":"CJ Shi","year":"2025","unstructured":"Shi CJ, Pang FX, Lei YH, Deng LQ, Pan FZ, Liang ZQ, et al. 5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1\/SLC7A11-mediated ferroptosis. Drug Resist Updat. 2025;78:101181.","journal-title":"Drug Resist Updat"},{"issue":"1","key":"4302_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07794-8","volume":"16","author":"K Wu","year":"2025","unstructured":"Wu K, Guo Z, Fu Y, Yang S, Pan Y, Yan R, et al. UBE4B promotes gastric cancer proliferation and metastasis by mediating FAT4 ubiquitination and degradation. Cell Death Dis. 2025;16(1):551.","journal-title":"Cell Death Dis"},{"issue":"6","key":"4302_CR26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2413126122","volume":"122","author":"M Takikawa","year":"2025","unstructured":"Takikawa M, Nakano A, Krishnaraj J, Tabata Y, Watanabe Y, Okabe A, et al. Extrinsic induction of apoptosis and tumor suppression via the p53-Reprimo-Hippo-YAP\/TAZ-p73 pathway. Proc Natl Acad Sci U S A. 2025;122(6):e2413126122.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"4302_CR27","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1002\/cam4.4977","volume":"12","author":"Y Ning","year":"2023","unstructured":"Ning Y, Yang Y, Zheng H, Zhan Y, Zang H, Wen Q, et al. Increased expression of FAT4 suppress metastasis of lung adenocarcinoma through regulating MAPK pathway and associated with immune cells infiltration. Cancer Med. 2023;12(2):1616\u201329.","journal-title":"Cancer Med"},{"issue":"11","key":"4302_CR28","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1002\/cac2.12471","volume":"43","author":"A Zhuang","year":"2023","unstructured":"Zhuang A, Gu X, Ge T, Wang S, Ge S, Chai P, et al. Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m(6) A RNA methylation in ocular melanoma. Cancer Commun (Lond). 2023;43(11):1185\u2013206.","journal-title":"Cancer Commun (Lond)"},{"issue":"1","key":"4302_CR29","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s12079-016-0355-5","volume":"11","author":"M Pilehchian Langroudi","year":"2017","unstructured":"Pilehchian Langroudi M, Nikbakhsh N, Samadani AA, Fattahi S, Taheri H, Shafaei S, et al. FAT4 hypermethylation and grade dependent downregulation in gastric adenocarcinoma. J Cell Commun Signal. 2017;11(1):69\u201375.","journal-title":"J Cell Commun Signal"},{"key":"4302_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156840","volume":"143","author":"J Zheng","year":"2025","unstructured":"Zheng J, Liu Y, Zhu F, Liu S, Cai Z, Liu M, et al. Picropodophyllin induces ferroptosis via blockage of AKT\/NRF2\/SLC7A11 and AKT\/NRF2\/SLC40A1 axes in hepatocellular carcinoma as a natural IGF1R inhibitor. Phytomedicine. 2025;143:156840.","journal-title":"Phytomedicine"},{"key":"4302_CR31","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-025-04423-1","author":"Y Gui","year":"2025","unstructured":"Gui Y, Deng S, Li J, Zuo D, Fan H. Ononin induces ferroptosis in colorectal cancer cells via the PI3K\/AKT\/Nrf2 pathway to enhance anti-cancer immunotherapy. Naunyn Schmiedebergs Arch Pharmacol. 2025. https:\/\/doi.org\/10.1007\/s00210-025-04423-1.","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"issue":"4","key":"4302_CR32","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1080\/08923973.2022.2160731","volume":"45","author":"L Wang","year":"2023","unstructured":"Wang L, Wang J, Chen L. TIMP1 represses sorafenib-triggered ferroptosis in colorectal cancer cells by activating the PI3K\/Akt signaling pathway. Immunopharmacol Immunotoxicol. 2023;45(4):419\u201325.","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"4302_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2026.111218","author":"L Xu","year":"2026","unstructured":"Xu L, Ning J, Wang J, Jiang P, Zhang X, Cheng F. CEP55 promotes prostate cancer progression via TPX2-dependent activation of AURKA\/PI3K\/AKT signaling and inhibition of ferroptosis. J Biol Chem. 2026. https:\/\/doi.org\/10.1016\/j.jbc.2026.111218.","journal-title":"J Biol Chem"},{"issue":"11\u201312","key":"4302_CR34","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/s41417-018-0066-6","volume":"26","author":"SY Li","year":"2019","unstructured":"Li SY, Wang H, Mai HF, Li GF, Chen SJ, Li GS, et al. Down-regulated long non-coding RNA RNAZFHX4-AS1 suppresses invasion and migration of breast cancer cells via FAT4-dependent Hippo signaling pathway. Cancer Gene Ther. 2019;26(11\u201312):374\u201387.","journal-title":"Cancer Gene Ther"},{"issue":"1","key":"4302_CR35","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-022-01934-2","volume":"40","author":"Y Yang","year":"2022","unstructured":"Yang Y, Li Y, Yang Q, Liu Z, Chang X, Yang H, et al. FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228\/Cer cells. Med Oncol. 2022;40(1):64.","journal-title":"Med Oncol"}],"container-title":["Clinical and Translational Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-026-04302-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12094-026-04302-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-026-04302-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T11:04:41Z","timestamp":1787396681000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12094-026-04302-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,14]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["4302"],"URL":"https:\/\/doi.org\/10.1007\/s12094-026-04302-y","relation":{},"ISSN":["1699-3055"],"issn-type":[{"value":"1699-3055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,14]]},"assertion":[{"value":"16 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that this study was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal procedures were approved by the Laboratory Animal Ethics Committee of Zhongke Industrial Holdings (Shenzhen) Ltd. (Approval No. 202400170).","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Patient consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}}]}}