{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:09:50Z","timestamp":1774285790702,"version":"3.50.1"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":37,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"DOI":"10.1007\/s12672-026-04501-7","type":"journal-article","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T09:54:02Z","timestamp":1771062842000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell RNA sequencing combined with single-cell genome-wide association study identifies SF3B4 as a hub gene in hepatocellular carcinoma progression"],"prefix":"10.1007","volume":"17","author":[{"given":"Fujun","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihong","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijian","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haibo","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"issue":"10","key":"4501_CR1","doi-asserted-by":"publisher","DOI":"10.1177\/0300060520943415","volume":"48","author":"SY Wang","year":"2020","unstructured":"Wang SY, Yin L, Wang C, Ma MP. Atypical magnetic resonance imaging features and differential diagnosis of hepatocellular carcinoma. J Int Med Res. 2020;48(10):300060520943415.","journal-title":"J Int Med Res"},{"issue":"10360","key":"4501_CR2","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/S0140-6736(22)01200-4","volume":"400","author":"A Vogel","year":"2022","unstructured":"Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400(10360):1345\u201362.","journal-title":"Lancet"},{"issue":"1","key":"4501_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"JM Llovet","year":"2021","unstructured":"Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.","journal-title":"Nat Rev Dis Primers"},{"issue":"1","key":"4501_CR4","first-page":"6","volume":"55","author":"T Feng","year":"2024","unstructured":"Feng T, Yang X, Wang Q, Liu X. Hepatocellular carcinoma-derived exosomes: key players in intercellular communication within the tumor microenvironment. Sichuan Da Xue Xue Bao Yi Xue Ban. 2024;55(1):6\u201312.","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"4501_CR5","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.2147\/JHC.S462168","volume":"11","author":"YK Li","year":"2024","unstructured":"Li YK, Wu S, Wu YS, Zhang WH, Wang Y, Li YH, et al. Portal venous and hepatic arterial coefficients predict post-hepatectomy overall and recurrence-free survival in patients with hepatocellular carcinoma: a retrospective study. J Hepatocell Carcinoma. 2024;11:1389\u2013402.","journal-title":"J Hepatocell Carcinoma"},{"issue":"8","key":"4501_CR6","first-page":"928","volume":"22","author":"J Xiang","year":"2025","unstructured":"Xiang J, Li Y, Mei S, Ou Z, Wang L, Ke Y, et al. Novel diagnostic and therapeutic strategies based on PANoptosis for hepatocellular carcinoma. Cancer Biol Med. 2025;22(8):928\u201339.","journal-title":"Cancer Biol Med"},{"issue":"11","key":"4501_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0166157","volume":"11","author":"MT Lin","year":"2016","unstructured":"Lin MT, Wang CC, Cheng YF, Eng HL, Yen YH, Tsai MC, et al. Comprehensive comparison of multiple-detector computed tomography and dynamic magnetic resonance imaging in the diagnosis of hepatocellular carcinoma with varying degrees of fibrosis. PLoS ONE. 2016;11(11):e0166157.","journal-title":"PLoS ONE"},{"issue":"1","key":"4501_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.iliver.2025.100147","volume":"4","author":"N Gao","year":"2025","unstructured":"Gao N, Wang D, Ma X, Lv F, Ren X. Contrast-enhanced US and contrast-enhanced CT for diagnosis of focal liver lesions in liver transplant recipients: a comparative study. Iliver. 2025;4(1):100147.","journal-title":"Iliver"},{"key":"4501_CR9","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.cytogfr.2024.08.006","volume":"79","author":"B Yu","year":"2024","unstructured":"Yu B, Ma W. Biomarker discovery in hepatocellular carcinoma (HCC) for personalized treatment and enhanced prognosis. Cytokine Growth Factor Rev. 2024;79:29\u201338.","journal-title":"Cytokine Growth Factor Rev"},{"key":"4501_CR10","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70018","author":"D Moris","year":"2025","unstructured":"Moris D, Martinino A, Schiltz S, Allen PJ, Barbas A, Sudan D, et al. Advances in the treatment of hepatocellular carcinoma: an overview of the current and evolving therapeutic landscape for clinicians. CA Cancer J Clin. 2025. https:\/\/doi.org\/10.3322\/caac.70018.","journal-title":"CA Cancer J Clin"},{"issue":"3","key":"4501_CR11","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/s41571-021-00573-2","volume":"19","author":"JM Llovet","year":"2022","unstructured":"Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151\u201372.","journal-title":"Nat Rev Clin Oncol"},{"issue":"5","key":"4501_CR12","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1080\/14737140.2025.2489651","volume":"25","author":"QB Wang","year":"2025","unstructured":"Wang QB, Li J, Zhang ZJ, Li YK, Liang YB, Chen XM, et al. The effectiveness and safety of therapies for hepatocellular carcinoma with tumor thrombus in the hepatic vein, inferior vena cave and\/or right atrium: a systematic review and single-arm meta-analysis. Expert Rev Anticancer Ther. 2025;25(5):561\u201370.","journal-title":"Expert Rev Anticancer Ther"},{"issue":"49","key":"4501_CR13","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000040769","volume":"103","author":"H Kwon","year":"2024","unstructured":"Kwon H, Kang E, Kim S, Baeck Y, Bark I, Cho J. Predicting prognosis prior to the combination of atezolizumab and bevacizumab on unresectable HCC: analysis and comparison of tumor heterogeneity at CT and Gd-EOB-DTPA hepatobiliary MR imaging. Medicine (Baltimore). 2024;103(49):e40769.","journal-title":"Medicine (Baltimore)"},{"issue":"8","key":"4501_CR14","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1016\/j.celrep.2019.10.045","volume":"29","author":"A Sharma","year":"2019","unstructured":"Sharma A, Merritt E, Hu X, Cruz A, Jiang C, Sarkodie H, et al. Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors. Cell Rep. 2019;29(8):2164-2174.e2165.","journal-title":"Cell Rep"},{"issue":"3","key":"4501_CR15","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1080\/15592294.2016.1277297","volume":"12","author":"RA Hlady","year":"2017","unstructured":"Hlady RA, Zhou D, Puszyk W, Roberts LR, Liu C, Robertson KD. Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer. Epigenetics. 2017;12(3):215\u201325.","journal-title":"Epigenetics"},{"issue":"15","key":"4501_CR16","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(15):1450\u201362.","journal-title":"N Engl J Med"},{"issue":"8062","key":"4501_CR17","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/s41586-025-08717-5","volume":"641","author":"Y Shen","year":"2025","unstructured":"Shen Y, Bai X, Zhang Q, Liang X, Jin X, Zhao Z, et al. Oncolytic virus VG161 in refractory hepatocellular carcinoma. Nature. 2025;641(8062):503\u201311.","journal-title":"Nature"},{"issue":"5","key":"4501_CR18","doi-asserted-by":"publisher","DOI":"10.1590\/1806-9282.20241408","volume":"71","author":"A Ogul","year":"2025","unstructured":"Ogul A, Birsenogul I, Kelle AP, Solmaz AA, Coskun Y, Yetisir AE, et al. Importance of 18F-fluorodeoxyglucose positron emission tomography\/computed tomography heterogeneity indices in non-small cell lung cancer. Rev Assoc Med Bras (1992). 2025;71(5):e20241408.","journal-title":"Rev Assoc Med Bras (1992)"},{"key":"4501_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s13000-015-0313-1","volume":"10","author":"A Helal Tel","year":"2015","unstructured":"Helal Tel A, Radwan NA, Shaker M. Extrahepatic metastases as initial manifestations of hepatocellular carcinoma: an Egyptian experience. Diagn Pathol. 2015;10:82.","journal-title":"Diagn Pathol"},{"issue":"4","key":"4501_CR20","doi-asserted-by":"publisher","DOI":"10.14309\/crj.0000000000000057","volume":"6","author":"M Silva","year":"2019","unstructured":"Silva M, Coelho R, Rios E, Gomes S, Carneiro F, Macedo G. Breast metastasis from a combined hepatocellular-cholangiocarcinoma. ACG Case Rep J. 2019;6(4):e00057.","journal-title":"ACG Case Rep J"},{"issue":"5","key":"4501_CR21","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/s41571-025-01003-3","volume":"22","author":"E Boxer","year":"2025","unstructured":"Boxer E, Feigin N, Tschernichovsky R, Darnell NG, Greenwald AR, Hoefflin R, et al. Emerging clinical applications of single-cell RNA sequencing in oncology. Nat Rev Clin Oncol. 2025;22(5):315\u201326.","journal-title":"Nat Rev Clin Oncol"},{"issue":"6","key":"4501_CR22","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41573-023-00688-4","volume":"22","author":"B Van de Sande","year":"2023","unstructured":"Van de Sande B, Lee JS, Mutasa-Gottgens E, Naughton B, Bacon W, Manning J, et al. Applications of single-cell RNA sequencing in drug discovery and development. Nat Rev Drug Discov. 2023;22(6):496\u2013520.","journal-title":"Nat Rev Drug Discov"},{"key":"4501_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.643375","volume":"11","author":"K Wang","year":"2021","unstructured":"Wang K, Liu M, Wang HW, Jin KM, Yan XL, Bao Q, et al. Mutated DNA damage repair pathways are prognostic and chemosensitivity markers for resected colorectal cancer liver metastases. Front Oncol. 2021;11:643375.","journal-title":"Front Oncol"},{"key":"4501_CR24","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.semcancer.2021.02.015","volume":"82","author":"LK Chan","year":"2022","unstructured":"Chan LK, Tsui YM, Ho DW, Ng IO. Cellular heterogeneity and plasticity in liver cancer. Semin Cancer Biol. 2022;82:134\u201349.","journal-title":"Semin Cancer Biol"},{"key":"4501_CR25","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030592","author":"M Ye","year":"2023","unstructured":"Ye M, Li X, Chen L, Mo S, Liu J, Huang T, et al. A high-throughput sequencing data-based classifier reveals the metabolic heterogeneity of hepatocellular carcinoma. Cancers (Basel). 2023. https:\/\/doi.org\/10.3390\/cancers15030592.","journal-title":"Cancers (Basel)"},{"issue":"1","key":"4501_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-81481-0","volume":"14","author":"X Wang","year":"2024","unstructured":"Wang X, Li P, Ji H, Xu Z, Xing H. Single-cell transcriptomics reveals over-activated reactive oxygen species pathway in hepatocytes in the development of hepatocellular carcinoma. Sci Rep. 2024;14(1):29809.","journal-title":"Sci Rep"},{"issue":"3","key":"4501_CR27","first-page":"3227","volume":"18","author":"C Zheng","year":"2019","unstructured":"Zheng C, Quan R, Xia EJ, Bhandari A, Zhang X. Original tumour suppressor gene polycystic kidney and hepatic disease 1-like 1 is associated with thyroid cancer cell progression. Oncol Lett. 2019;18(3):3227\u201335.","journal-title":"Oncol Lett"},{"issue":"1","key":"4501_CR28","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.6796","volume":"13","author":"L Han","year":"2024","unstructured":"Han L, Gong F, Wu X, Tang W, Bao H, Wang Y, et al. Comprehensive characterization of PKHD1 mutation in human colon cancer. Cancer Med. 2024;13(1):e6796.","journal-title":"Cancer Med"},{"issue":"14","key":"4501_CR29","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.7150\/ijms.95964","volume":"21","author":"T Shang","year":"2024","unstructured":"Shang T, Chen X, Xue H, Wu Y, Lin S, Zhu Y. The PKHD1 gene inhibits tumor proliferation and invasion in intrahepatic cholangiocarcinoma by activating the Notch pathway. Int J Med Sci. 2024;21(14):2655\u201363.","journal-title":"Int J Med Sci"},{"issue":"3","key":"4501_CR30","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1055\/s-0040-1708876","volume":"40","author":"M Matsuda","year":"2020","unstructured":"Matsuda M, Seki E. Hepatic stellate cell-macrophage crosstalk in liver fibrosis and carcinogenesis. Semin Liver Dis. 2020;40(3):307\u201320.","journal-title":"Semin Liver Dis"},{"key":"4501_CR31","doi-asserted-by":"publisher","DOI":"10.3390\/cells9092027","author":"L Kaps","year":"2020","unstructured":"Kaps L, Schuppan D. Targeting cancer associated fibroblasts in liver fibrosis and liver cancer using nanocarriers. Cells. 2020. https:\/\/doi.org\/10.3390\/cells9092027.","journal-title":"Cells"},{"key":"4501_CR32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00016","volume":"11","author":"Y Xie","year":"2020","unstructured":"Xie Y, Zhang Y, Wei X, Zhou C, Huang Y, Zhu X, et al. Jianpi huayu decoction attenuates the immunosuppressive status of H(22) hepatocellular carcinoma-bearing mice: by targeting myeloid-derived suppressor cells. Front Pharmacol. 2020;11:16.","journal-title":"Front Pharmacol"},{"issue":"1","key":"4501_CR33","doi-asserted-by":"publisher","first-page":"217","DOI":"10.7150\/jca.48983","volume":"12","author":"L Wang","year":"2021","unstructured":"Wang L, Yan K, He X, Zhu H, Song J, Chen S, et al. LRP1B or TP53 mutations are associated with higher tumor mutational burden and worse survival in hepatocellular carcinoma. J Cancer. 2021;12(1):217\u201323.","journal-title":"J Cancer"},{"issue":"6","key":"4501_CR34","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.62347\/AHXI2343","volume":"15","author":"T Wu","year":"2025","unstructured":"Wu T, Xiao Z, Su B, Yan Z, Zhao Y, Huang C, et al. Splicing factor 3b subunit 4 (SF3b4) is mediated by EP300 and CREBBP to promote colorectal cancer (CRC) proliferation by enhancing autophagy. Am J Cancer Res. 2025;15(6):2826\u201342.","journal-title":"Am J Cancer Res"},{"key":"4501_CR35","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ebiom.2018.10.067","volume":"38","author":"Z Liu","year":"2018","unstructured":"Liu Z, Li W, Pang Y, Zhou Z, Liu S, Cheng K, et al. SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma. EBioMedicine. 2018;38:57\u201368.","journal-title":"EBioMedicine"},{"issue":"1","key":"4501_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-025-06420-7","volume":"23","author":"H Huang","year":"2025","unstructured":"Huang H, Fang Y, Li Z, Qu S, Yuan B, Gan K, et al. SF3B4 regulates proliferation and apoptosis in hepatocellular carcinoma via alternative splicing and interaction with TRIM28 and SETD5. J Transl Med. 2025;23(1):441.","journal-title":"J Transl Med"},{"issue":"2","key":"4501_CR37","doi-asserted-by":"publisher","first-page":"57","DOI":"10.5483\/BMBRep.2018.51.2.021","volume":"51","author":"Q Shen","year":"2018","unstructured":"Shen Q, Nam SW. SF3B4 as an early-stage diagnostic marker and driver of hepatocellular carcinoma. BMB Rep. 2018;51(2):57\u20138.","journal-title":"BMB Rep"},{"issue":"41","key":"4501_CR38","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adw7181","volume":"11","author":"Y Guo","year":"2025","unstructured":"Guo Y, Xu M, Xue H, Ding X, Wong AM, Lin N, et al. Genome-wide CRISPR screen identifies splicing factor SF3B4 in driving hepatocellular carcinoma. Sci Adv. 2025;11(41):eadw7181.","journal-title":"Sci Adv"},{"issue":"5","key":"4501_CR39","first-page":"2139","volume":"36","author":"T Iguchi","year":"2016","unstructured":"Iguchi T, Komatsu H, Masuda T, Nambara S, Kidogami S, Ogawa Y, et al. Increased copy number of the gene encoding SF3B4 indicates poor prognosis in hepatocellular carcinoma. Anticancer Res. 2016;36(5):2139\u201344.","journal-title":"Anticancer Res"},{"key":"4501_CR40","doi-asserted-by":"publisher","first-page":"2055","DOI":"10.2147\/JHC.S544589","volume":"12","author":"QB Wang","year":"2025","unstructured":"Wang QB, Luo WL, Li YK, Li J, Yang ZS, Zhao K, et al. Tumor compression of the hepatic or portal vein predicts the presence of microvascular invasion and satellite nodules in hepatocellular carcinoma: a retrospective study. J Hepatocell Carcinoma. 2025;12:2055\u201367.","journal-title":"J Hepatocell Carcinoma"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-026-04501-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-026-04501-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-026-04501-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T16:33:21Z","timestamp":1774283601000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-026-04501-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,14]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4501"],"URL":"https:\/\/doi.org\/10.1007\/s12672-026-04501-7","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,14]]},"assertion":[{"value":"3 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 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":"The experimental protocol of this study was approved by the Ethics Committee of Henan Medical University in accordance with the World Medical Association Declaration of Helsinki and the relevant ethical guidelines and regulations for medical research involving human participants. All procedures involving human tissue samples were conducted strictly following the approved protocol and ethical standards of the aforementioned committee. Informed written consent was obtained from all participants prior to sample collection, and all personal identifying information of participants was de-identified to ensure privacy protection.","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":"461"}}