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The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We performed integrated multiomics analysis in 116 iCCA samples, including whole\u2010exome sequencing, bulk RNA\u2010sequencing and proteome analysis. Based on the non\u2010negative matrix factorization method and the protein abundance of metabolic genes in human genome\u2010scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5\u2010ethynyl\u20102'\u2010deoxyuridine (EdU) assay, colony formation assay, RNA\u2010sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase \u03b1 (DGKA) in iCCA cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Three metabolic subtypes (S1\u2010S3) with subtype\u2010specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune\u2010suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (\n                      <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                      )\/AT\u2010rich interactive domain 1A (\n                      <jats:italic toggle=\"yes\">ARID1A<\/jats:italic>\n                      ) mutations. Among the S2 subtype\u2010specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen\u2010activated protein kinase (MAPK) signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p xml:lang=\"en\">Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12513","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T22:49:46Z","timestamp":1703458186000},"page":"226-250","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase \u03b1 (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma"],"prefix":"10.34133","volume":"44","author":[{"given":"Weiren","family":"Liu","sequence":"first","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1032-7612","authenticated-orcid":false,"given":"Qianfu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Tao","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weifeng","family":"Qu","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushan","family":"Hou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run","family":"Huang","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. 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China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Tang","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Shi","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital","place":["Shanghai, P. R. China"]},{"name":"Fudan University","place":["Shanghai, P. R. China"]},{"name":"Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education","place":["Shanghai, P. R. China"]},{"name":"Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2023,12,24]]},"reference":[{"issue":"2","key":"e_1_3_2_2_2","first-page":"198","article-title":"Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians","volume":"73","author":"Moris D","year":"2022","unstructured":"Moris D, Palta M, Kim C, Allen PJ, Morse MA, Lidsky ME. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 2022;73((2)):198\u2013222.","journal-title":"CA Cancer J Clin"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"issue":"2","key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nrclinonc.2017.157","article-title":"Cholangiocarcinoma \u2010 evolving concepts and therapeutic strategies","volume":"15","author":"Rizvi S","year":"2018","unstructured":"Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma \u2010 evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15((2)):95\u2013111.","journal-title":"Nat Rev Clin Oncol"},{"issue":"1","key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12876-016-0527-z","article-title":"Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database","volume":"16","author":"Yao KJ","year":"2016","unstructured":"Yao KJ, Jabbour S, Parekh N, Lin Y, Moss RA. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol. 2016;16((1)):117.","journal-title":"BMC Gastroenterol"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.12.006"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30157-1"},{"issue":"5","key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S1470-2045(20)30109-1","article-title":"Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open\u2010label, phase 2 study","volume":"21","author":"Abou\u2010Alfa GK","year":"2020","unstructured":"Abou\u2010Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al\u2010Rajabi R, et\u00a0al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open\u2010label, phase 2 study. Lancet Oncol. 2020;21((5)):671\u2013684.","journal-title":"Lancet Oncol"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32624"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-004892"},{"issue":"1","key":"e_1_3_2_11_2","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/s41467-022-29164-0","article-title":"Single\u2010cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma","volume":"13","author":"Song G","year":"2022","unstructured":"Song G, Shi Y, Meng L, Ma J, Huang S, Zhang J, et\u00a0al. Single\u2010cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma. Nat Commun. 2022;13((1)):1642.","journal-title":"Nat Commun"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.02.045"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00378-6"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1211"},{"issue":"1","key":"e_1_3_2_16_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12943-021-01316-8","article-title":"The cancer metabolic reprogramming and immune response","volume":"20","author":"Xia L","year":"2021","unstructured":"Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, et\u00a0al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20((1)):28.","journal-title":"Mol Cancer"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0299-0"},{"issue":"14","key":"e_1_3_2_18_2","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2010Wheeler transform","volume":"25","author":"Li H","year":"2009","unstructured":"Li H, Durbin R. Fast and accurate short read alignment with Burrows\u2010Wheeler transform. Bioinformatics. 2009;25((14)):1754\u20131760.","journal-title":"Bioinformatics"},{"issue":"1110","key":"e_1_3_2_19_2","first-page":"1","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Van der Auwera GA","year":"2013","unstructured":"Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy\u2010Moonshine A, et\u00a0al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;43((1110)):1\u201333.","journal-title":"Curr Protoc Bioinformatics"},{"issue":"4","key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias\u2010aware quantification of transcript expression","volume":"14","author":"Patro R","year":"2017","unstructured":"Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias\u2010aware quantification of transcript expression. 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