Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC
BackgroundSorafenib is a first-line treatment for hepatocellular carcinoma (HCC); however, acquired resistance often results in a poor prognosis, indicating a need for more effective therapies. Sorafenib induces cell death through an iron-dependent mechanism known as ferroptosis, which is closely as...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1464852/full |
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| author | Xue Li Xue Li Shimin Chen Shimin Chen Yuanyuan Shi Yuanjing Wang Yuanjing Wang Xuanzhe Wang Xuanzhe Wang Qian Lin Chao Wu Wenshuo Fang Peng Sun Leina Ma |
| author_facet | Xue Li Xue Li Shimin Chen Shimin Chen Yuanyuan Shi Yuanjing Wang Yuanjing Wang Xuanzhe Wang Xuanzhe Wang Qian Lin Chao Wu Wenshuo Fang Peng Sun Leina Ma |
| author_sort | Xue Li |
| collection | DOAJ |
| description | BackgroundSorafenib is a first-line treatment for hepatocellular carcinoma (HCC); however, acquired resistance often results in a poor prognosis, indicating a need for more effective therapies. Sorafenib induces cell death through an iron-dependent mechanism known as ferroptosis, which is closely associated with the onset and progression of HCC.MethodsThis study investigated the role of ACSL3 in sorafenib resistance and ferroptosis in HCC. The expression of ACSL3 was analyzed in HCC tissues and cell lines. Ferroptosis levels and cell viability were assessed in ACSL3-silenced HCC cells treated with sorafenib. The regulatory relationship between the transcription factor MEF2D and ACSL3 was evaluated using promoter binding assays and gene expression analysis.ResultsACSL3 was aberrantly expressed in HCC and promoted the progression of non-alcoholic fatty liver disease (NAFLD) to HCC. Elevated ACSL3 expression inhibited ferroptosis and enhanced resistance to sorafenib. The transcription factor MEF2D directly regulated the upregulation of ACSL3 expression. MEF2D bound to the promoter regions of ACSL3 to enhance its transcription and negatively regulate ferroptosis in HCC.ConclusionThis study demonstrated for the first time that MEF2D regulated ACSL3 expression and mediated sorafenib resistance by inhibiting ferroptosis in HCC, providing a potential therapeutic target for improving HCC outcomes. |
| format | Article |
| id | doaj-art-c418d79ac8fb4549a65fa3bcf9bc4c2a |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-c418d79ac8fb4549a65fa3bcf9bc4c2a2025-08-20T02:36:59ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-12-011510.3389/fphar.2024.14648521464852Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCCXue Li0Xue Li1Shimin Chen2Shimin Chen3Yuanyuan Shi4Yuanjing Wang5Yuanjing Wang6Xuanzhe Wang7Xuanzhe Wang8Qian Lin9Chao Wu10Wenshuo Fang11Peng Sun12Leina Ma13School of Basic Medicine, Qingdao University, Qingdao, ChinaQingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaSchool of Basic Medicine, Qingdao University, Qingdao, ChinaQingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaBiomedical center, Qingdao university, Qingdao, ChinaSchool of Basic Medicine, Qingdao University, Qingdao, ChinaQingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaSchool of Basic Medicine, Qingdao University, Qingdao, ChinaQingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaQingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaHepatobiliary Surgery Department 1, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, ChinaDepartment of Clinical Laboratory, Maternity and Child Care Hospital, Weifang, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, ChinaQingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaBackgroundSorafenib is a first-line treatment for hepatocellular carcinoma (HCC); however, acquired resistance often results in a poor prognosis, indicating a need for more effective therapies. Sorafenib induces cell death through an iron-dependent mechanism known as ferroptosis, which is closely associated with the onset and progression of HCC.MethodsThis study investigated the role of ACSL3 in sorafenib resistance and ferroptosis in HCC. The expression of ACSL3 was analyzed in HCC tissues and cell lines. Ferroptosis levels and cell viability were assessed in ACSL3-silenced HCC cells treated with sorafenib. The regulatory relationship between the transcription factor MEF2D and ACSL3 was evaluated using promoter binding assays and gene expression analysis.ResultsACSL3 was aberrantly expressed in HCC and promoted the progression of non-alcoholic fatty liver disease (NAFLD) to HCC. Elevated ACSL3 expression inhibited ferroptosis and enhanced resistance to sorafenib. The transcription factor MEF2D directly regulated the upregulation of ACSL3 expression. MEF2D bound to the promoter regions of ACSL3 to enhance its transcription and negatively regulate ferroptosis in HCC.ConclusionThis study demonstrated for the first time that MEF2D regulated ACSL3 expression and mediated sorafenib resistance by inhibiting ferroptosis in HCC, providing a potential therapeutic target for improving HCC outcomes.https://www.frontiersin.org/articles/10.3389/fphar.2024.1464852/fullACSL3MEF2DHCCferroptosissorafenib resistance |
| spellingShingle | Xue Li Xue Li Shimin Chen Shimin Chen Yuanyuan Shi Yuanjing Wang Yuanjing Wang Xuanzhe Wang Xuanzhe Wang Qian Lin Chao Wu Wenshuo Fang Peng Sun Leina Ma Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC Frontiers in Pharmacology ACSL3 MEF2D HCC ferroptosis sorafenib resistance |
| title | Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC |
| title_full | Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC |
| title_fullStr | Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC |
| title_full_unstemmed | Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC |
| title_short | Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC |
| title_sort | transcription factor mef2d regulates aberrant expression of acsl3 and enhances sorafenib resistance by inhibiting ferroptosis in hcc |
| topic | ACSL3 MEF2D HCC ferroptosis sorafenib resistance |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1464852/full |
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