biostudies-literatureNakano YTakeda Science FoundationJapan Agency for Medical Research and DevelopmentOITA Cancer Research Foundation3352-3366https://www.ebi.ac.uk/biostudies/studies/S-EPMC12666459biostudies-literatureUnknown116(12)Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with poor prognosis and significant molecular heterogeneity. This study investigates the role of tumor-specific enhancers in metabolic reprogramming, focusing on glucose-6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Using native elongating transcript-cap analysis of gene expression and single-cell RNA sequencing, tumor-specific enhancers driving G6PD overexpression were identified in ICC tumor epithelial cells. Functional assays demonstrated that G6PD promotes tumor proliferation by enhancing PPP activity and maintaining redox homeostasis, which provides NADPH to counter oxidative stress. Enhancer knockdown disrupted G6PD expression and PPP activity, increasing reactive oxygen species levelsCancer scienceEpigenetic Regulation of G6PD Drives Metabolic Reprogramming in Intrahepatic Cholangiocarcinoma.PMC1266645922ama221501h000123ck0106800h001Eguchi HIkehara TKawata KUemura MOgino TMasuda TDoki YSaito HOfuchi TNakano YHashimoto MAbe TMimori KTobo TTanaka MSakamoto TfalseEpigenetic Regulation of G6PD Drives Metabolic Reprogramming in Intrahepatic Cholangiocarcinoma.Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with poor prognosis and significant molecular heterogeneity. This study investigates the role of tumor-specific enhancers in metabolic reprogramming, focusing on glucose-6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Using native elongating transcript-cap analysis of gene expression and single-cell RNA sequencing, tumor-specific enhancers driving G6PD overexpression were identified in ICC tumor epithelial cells. Functional assays demonstrated that G6PD promotes tumor proliferation by enhancing PPP activity and maintaining redox homeostasis, which provides NADPH to counter oxidative stress. Enhancer knockdown disrupted G6PD expression and PPP activity, increasing reactive oxygen species levels2025-01-01T00:00:00Z2025 Dec2026-07-15T14:35:06.497Z2026-07-06T03:08:58.627ZS-EPMC126664594105438010.1111/cas.70202