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Lipid metabolism reprogramming drives HCC progression; however, the functional crosstalk between CYP19A1, GPER1, and lipid metabolic dysregulation in HCC remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Integrated analyses of The Cancer Genome Atlas Liver Hepatocellular Carcinoma data were performed. Clinical validation, functional assays, rescue experiments, in vivo xenografts, and molecular docking were conducted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CYP19A1 was identified as a prognostic hub in HCC, with overexpression correlating with advanced T\/BCLC stages (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and poor survival (log-rank\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Gene set enrichment analysis linked CYP19A1 to dysregulated lipid metabolism, pro-tumorigenic signaling, and immune infiltration. GPER1 was found to be a critical effector of CYP19A1, mediating its effects on proliferation, migration, invasion, epithelial\u2013mesenchymal transition, and protein kinase B activation. CYP19A1 knockdown reduced tumor burden in vivo, whereas\n                      <jats:italic>GPER1<\/jats:italic>\n                      overexpression rescued this phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The CYP19A1-GPER1 axis represents a critical oncogenic driver in HCC, providing a mechanistic insight to guide future therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08246-3","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T02:06:48Z","timestamp":1779156408000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of the CYP19A1-GPER1 axis as a critical oncogenic driver in hepatocellular carcinoma via AKT activation"],"prefix":"10.1186","volume":"24","author":[{"given":"Hang","family":"Zhai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jicai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjie","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangquan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjie","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"issue":"1","key":"8246_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2174\/157488512800389164","volume":"7","author":"I Ali","year":"2012","unstructured":"Ali I, Wani WA, Saleem K, Haque A. 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