Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis
Abstract Targeting cholesterol metabolism is a novel direction for tumor therapy. Unfortunately, the current use of statins for hepatocellular carcinoma (HCC) is controversial. Herein, farnesyl‐diphosphate farnesyltransferase 1 (FDFT1) is identified as a novel target for treating HCC and a potential...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411719 |
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| author | Dong Cai Guo‐Chao Zhong Xin Dai Zhibo Zhao Menglin Chen Jiejun Hu Zhenru Wu Lve Cheng Shengwei Li Jianping Gong |
| author_facet | Dong Cai Guo‐Chao Zhong Xin Dai Zhibo Zhao Menglin Chen Jiejun Hu Zhenru Wu Lve Cheng Shengwei Li Jianping Gong |
| author_sort | Dong Cai |
| collection | DOAJ |
| description | Abstract Targeting cholesterol metabolism is a novel direction for tumor therapy. Unfortunately, the current use of statins for hepatocellular carcinoma (HCC) is controversial. Herein, farnesyl‐diphosphate farnesyltransferase 1 (FDFT1) is identified as a novel target for treating HCC and a potential alternative to statins. Twenty‐three key genes in cholesterol biosynthesis are screened, and FDFT1 is identified via public databases (The Cancer Genome Atlas, International Cancer Genome Consortium and Gene Expression Omnibus). Clinical samples reveal that FDFT1 is highly expressed in HCC tissues, and this phenotype is strongly associated with a poor prognosis. Functionally, FDFT1 knockdown inhibits the proliferation and metastasis of HCC cells and suppresses hepatocarcinogenesis in vitro and in vivo, whereas FDFT1 overexpression promotes HCC cell proliferation and metastasis. Mechanistically, FDFT1 downregulation decreases cholesterol and bile acid levels and then increases hepatocyte nuclear factor 4 alpha (HNF4A) transcriptional activity. Experiments indicate that HNF4A combines with the promoter of aldolase B (ALDOB) and promotes the ALDOB transcription and that ALDOB combines with AKT serine/threonine kinase 1 (AKT1) and inhibits AKT1 phosphorylation. Moreover, FDFT1 knockdown combined with AKT inhibitor (AZD5363) treatment shows remarkable therapeutic potential. FDFT1 inhibition reduces cholesterol and bile acid levels to delay HCC progression through the HNF4A/ALDOB/AKT1 axis. Thus, targeting FDFT1 may be a novel potential strategy for treating HCC. |
| format | Article |
| id | doaj-art-0541c05d571c46ccaa512fa9de4fa163 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-0541c05d571c46ccaa512fa9de4fa1632025-08-20T01:49:42ZengWileyAdvanced Science2198-38442025-03-011212n/an/a10.1002/advs.202411719Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 AxisDong Cai0Guo‐Chao Zhong1Xin Dai2Zhibo Zhao3Menglin Chen4Jiejun Hu5Zhenru Wu6Lve Cheng7Shengwei Li8Jianping Gong9Department of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaInstitute of Clinical Pathology Key Laboratory of Transplant Engineering and Immunology NHC West China Hospital Sichuan University Chengdu Sichuan 610041 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaInstitute of Clinical Pathology Key Laboratory of Transplant Engineering and Immunology NHC West China Hospital Sichuan University Chengdu Sichuan 610041 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaAbstract Targeting cholesterol metabolism is a novel direction for tumor therapy. Unfortunately, the current use of statins for hepatocellular carcinoma (HCC) is controversial. Herein, farnesyl‐diphosphate farnesyltransferase 1 (FDFT1) is identified as a novel target for treating HCC and a potential alternative to statins. Twenty‐three key genes in cholesterol biosynthesis are screened, and FDFT1 is identified via public databases (The Cancer Genome Atlas, International Cancer Genome Consortium and Gene Expression Omnibus). Clinical samples reveal that FDFT1 is highly expressed in HCC tissues, and this phenotype is strongly associated with a poor prognosis. Functionally, FDFT1 knockdown inhibits the proliferation and metastasis of HCC cells and suppresses hepatocarcinogenesis in vitro and in vivo, whereas FDFT1 overexpression promotes HCC cell proliferation and metastasis. Mechanistically, FDFT1 downregulation decreases cholesterol and bile acid levels and then increases hepatocyte nuclear factor 4 alpha (HNF4A) transcriptional activity. Experiments indicate that HNF4A combines with the promoter of aldolase B (ALDOB) and promotes the ALDOB transcription and that ALDOB combines with AKT serine/threonine kinase 1 (AKT1) and inhibits AKT1 phosphorylation. Moreover, FDFT1 knockdown combined with AKT inhibitor (AZD5363) treatment shows remarkable therapeutic potential. FDFT1 inhibition reduces cholesterol and bile acid levels to delay HCC progression through the HNF4A/ALDOB/AKT1 axis. Thus, targeting FDFT1 may be a novel potential strategy for treating HCC.https://doi.org/10.1002/advs.202411719bile acidcholesterolFDFT1hepatocellular carcinomaproliferation |
| spellingShingle | Dong Cai Guo‐Chao Zhong Xin Dai Zhibo Zhao Menglin Chen Jiejun Hu Zhenru Wu Lve Cheng Shengwei Li Jianping Gong Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis Advanced Science bile acid cholesterol FDFT1 hepatocellular carcinoma proliferation |
| title | Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis |
| title_full | Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis |
| title_fullStr | Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis |
| title_full_unstemmed | Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis |
| title_short | Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis |
| title_sort | targeting fdft1 reduces cholesterol and bile acid production and delays hepatocellular carcinoma progression through the hnf4a aldob akt1 axis |
| topic | bile acid cholesterol FDFT1 hepatocellular carcinoma proliferation |
| url | https://doi.org/10.1002/advs.202411719 |
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