{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:49:08Z","timestamp":1791521348678,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32422069"],"award-info":[{"award-number":["32422069"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Chronic inflammation is a hallmark of hepatocellular carcinoma (HCC) and is closely linked to aberrant arachidonic acid (AA) metabolism; however, whether AA mobilization is driven by defined upstream regulatory mechanisms and can be therapeutically targeted remains largely unresolved. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central regulator of AA\u2010dependent inflammatory signaling in hepatocarcinogenesis and a direct pharmacological target of nuciferine (NF). Using diethylnitrosamine (DEN)\/carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    )\u2010induced HCC mouse models with transcriptomic and lipidomic profiling, we show that cPLA2 activation is progressively elevated during tumorigenesis, leading to excessive eicosanoid production that fuels NF\u2010\u03baB\u2010driven inflammation. NF markedly suppresses tumor burden, fibrosis, and inflammatory signaling, accompanied by broad inhibition of AA metabolism. Mechanistically, NF directly binds to the C2 domain of cPLA2, disrupting Ca\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    \u2010dependent membrane translocation and attenuating its activation. Importantly,\n                    <jats:italic>Pla2g4a<\/jats:italic>\n                    deficiency significantly attenuates hepatocarcinogenesis and abolishes the therapeutic effects of NF, establishing cPLA2 as essential for its antitumor activity. In human HCC, increased cPLA2 activation correlates with increased AA metabolism, inflammatory signatures, and poor patient survival. These findings uncover cPLA2\u2010dependent AA metabolism as a critical inflammatory axis in HCC and identify NF as a direct cPLA2\u2010targeting agent, highlighting a pharmacologically actionable metabolic node for liver cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.78212","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:51:13Z","timestamp":1791517873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nuciferine Suppresses Inflammatory Hepatocarcinogenesis by Targeting cPLA2\u2010Dependent Arachidonic Acid Metabolism"],"prefix":"10.1002","author":[{"given":"Jing","family":"Sun","sequence":"first","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2836-0804","authenticated-orcid":false,"given":"Xinyan","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwei","family":"Luo","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6600-4673","authenticated-orcid":false,"given":"Yilang","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Dazhou Central Hospital  Dazhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0900-9285","authenticated-orcid":false,"given":"Tuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipak","family":"Panigrahy","sequence":"additional","affiliation":[{"name":"Center For Vascular Biology Research Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3057-6997","authenticated-orcid":false,"given":"Jianjun","family":"Deng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vegetable Biobreeding Institute of Vegetables and Flowers Chinese Academy of Agricultural Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Liao","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4410-9257","authenticated-orcid":false,"given":"Haixia","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung H.","year":"2021","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201064079\u20106"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32007"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010025\u201002378\u20108"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010018\u20100044\u2010z"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555\u2010018\u20109742\u20100"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201024\u20101611"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201021\u20104362"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201061448\u2010z"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010023\u201001391\u20106"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.12086"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1590\u20108658(01)80155\u20109"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44760"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108382"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(91)90556\u2010E"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092\u20108674(00)80744\u20108"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100943200"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(17)32440\u20107"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R057588"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2026.01.002"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/procel\/pwae014"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/hep.510270108","article-title":"Increased Renal and Vascular Cytosolic Phospholipase A2 Activity in Rats With Cirrhosis and Ascites","volume":"27","author":"Niederberger M.","year":"1998","journal-title":"Hepatology"},{"key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/hep.23703","article-title":"Cytosolic Phospholipase A2\u03b1 and Peroxisome Proliferator\u2010activated Receptor \u03b3 Signaling Pathway Counteracts Transforming Growth Factor \u03b2\u2013mediated Inhibition of Primary and Transformed Hepatocyte Growth\u2020","volume":"52","author":"Han C.","year":"2010","journal-title":"Hepatology"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201006\u20101445"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201006895\u20100"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010020\u201000443\u2010w"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010020\u201000114\u2010z"},{"issue":"4","key":"e_1_2_11_29_1","doi-asserted-by":"crossref","DOI":"10.31083\/IJVNR38103","article-title":"Ginkgo Biloba L. as a Potential Alternative Therapy to Improve the Management of Diabetes: An Overview on Phytochemical Insights, Mechanisms, and Therapeutic Applications","volume":"95","author":"Siam N. H.","year":"2025","journal-title":"International Journal for Vitamin and Nutrition Research"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202417225"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2023.106820"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2023.11.003"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.106002"},{"issue":"24","key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.3390\/foods13244038","article-title":"The Effect of Ice\u2010Binding Protein From Leucosporidium sp. AY30 (LeIBP) on the Physicochemical Quality and Microstructure of Largemouth Bass during Freeze\u2013Thaw Cycles","volume":"13","author":"Ren J.","year":"2024","journal-title":"Foods"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0482405"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007412117"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2020.10.021"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/btm2.10288"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2014.05.022"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.11.016"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010025\u201002363\u20100"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101774"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.1c00827"},{"key":"e_1_2_11_44_1","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1053\/jhep.2002.31774","article-title":"COX\u20102 Inhibits Fas\u2010mediated Apoptosis in Cholangiocarcinoma Cells","volume":"35","author":"Nzeako U. C.","year":"2002","journal-title":"Hepatology"},{"key":"e_1_2_11_45_1","doi-asserted-by":"crossref","DOI":"10.3389\/fchem.2023.1287570","article-title":"Dual COX\u20102\/5\u2010LOX inhibitors from Zanthoxylum simulans Inhibit Gastric Cancer Cells By Cross\u2010Mediating Thyroid, Estrogen, And Oxytocin Signaling Pathways","volume":"11","author":"Tian Y.\u2010Q.","year":"2024","journal-title":"Frontiers in Chemistry"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115866"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555\u2010018\u20109746\u20109"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S278514"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(93)90666\u2010E"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr200085w"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202411559"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.27.1168"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804492200"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708143200"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27072347"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201055536\u20109"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.21.14979"},{"key":"e_1_2_11_58_1","first-page":"17612","article-title":"Tissue Distribution Model and Pharmacokinetics of Nuciferine Based on UPLC\u2010MS\/MS and BP\u2010ANN","volume":"8","author":"Xu Y.","year":"2015","journal-title":"International journal of clinical and experimental medicine"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201084936\u20106"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2010.213"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010022\u201002531\u2010x"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.183"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010022\u201000549\u20105"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78212","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.78212","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78212","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:51:15Z","timestamp":1791517875000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.78212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":62,"alternative-id":["10.1002\/advs.78212"],"URL":"https:\/\/doi.org\/10.1002\/advs.78212","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2026-05-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e78212"}}