{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:46:07Z","timestamp":1793400367252,"version":"4.5.0"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"vor","delay-in-days":38,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82272975,82273238,82203796"],"award-info":[{"award-number":["82272975,82273238,82203796"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,31]]},"abstract":"<jats:p>\n                    Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1\u03b1 stability and activating the HIF-1\u03b1 signaling pathway. However, whether other metabolites regulate HIF-1\u03b1 stability remains unclear. Here, we reported that deficiency of the enzyme in phenylalanine\/tyrosine catabolism, glutathione\n                    <jats:italic>S<\/jats:italic>\n                    -transferase zeta 1 (\n                    <jats:italic>GSTZ1<\/jats:italic>\n                    ), led to accumulation of succinylacetone, which was structurally similar to \u03b1-ketoglutarate. Succinylacetone competed with \u03b1-ketoglutarate for prolyl hydroxylase domain 2 (PHD2) binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1\u03b1, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1\u03b1\/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1\u03b1 inhibitor combined with anti\u2013programmed cell death ligand 1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in\n                    <jats:italic>Gstz1<\/jats:italic>\n                    -knockout mice, suggesting a potentially actionable strategy for HCC treatment.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.164968","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T12:00:46Z","timestamp":1698753646000},"source":"Crossref","is-referenced-by-count":30,"title":["Signaling metabolite succinylacetone activates HIF-1\u03b1 and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma"],"prefix":"10.1172","volume":"8","author":[{"given":"Huating","family":"Luo","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"},{"name":"Department of Geriatrics, The First Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiujie","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The First Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Affiliated Hospital; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingzhu","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3201-6245","authenticated-orcid":true,"given":"Bin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0377-877X","authenticated-orcid":true,"given":"Luyi","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3425-1118","authenticated-orcid":true,"given":"Chang","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences, Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Xiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0137-1247","authenticated-orcid":true,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The First Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-8786","authenticated-orcid":true,"given":"Ni","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2006.06.002"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.025"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.08.025"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-022-00587-8"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2468"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/28867"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nm0603-677"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201695204"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.06.002"},{"issue":"8","key":"B11","first-page":"1764","article-title":"Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells","volume":"63","author":"Knowles","year":"2003","journal-title":"Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-019-0235-1"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610415200"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2004.11.022"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00378-6"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1211"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.06.017"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2020.153153"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2007.09.014"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840200513"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.13.4943-4951.2002"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019101964"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.995"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nm0603-669"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/359843a0"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00077-1"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1039\/C8CC00387D"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.09.015"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.52.34760"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0229276"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23540"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.465"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaz8534"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.06.009"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature08617"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1173362"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.06.048"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600200"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060713-035513"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.12.002"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-021-00438-0"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32023"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1543"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131916"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01102-5"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI156774"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2021.10.004"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1459-6"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31764-9"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3390\/genes14030693"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/164968\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:45:26Z","timestamp":1779140726000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/164968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":52,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12,8]]},"published-print":{"date-parts":[[2023,12,8]]}},"alternative-id":["10.1172\/jci.insight.164968"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.164968","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]},"article-number":"e164968"}}