Wenwen Huang, Haihong Hu, Sheng Cai, Xiaoli Zheng, Su Zeng
{"title":"m6A修饰的cyp1b1通过抑制铁下垂促进HCC细胞增殖。","authors":"Wenwen Huang, Haihong Hu, Sheng Cai, Xiaoli Zheng, Su Zeng","doi":"10.2174/0113892002387502250714112923","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>CYP1B1, a crucial drug-metabolizing enzyme, metabolizes both endogenous compounds and clinical drugs. The present study investigated the effects of CYP1B1 on the proliferation, migration, apoptosis, and ferroptosis of HCC cells. It further elucidated the regulatory role of m⁶A modification, particularly via the methyltransferase METTL14-in regulating CYP1B1 mRNA stability and translation efficiency.</p><p><strong>Methods: </strong>CCK-8, colony formation, wound healing, and transwell assays were employed to assess the role of CYP1B1 in HCC cell proliferation and migration. Ferroptosis-related assays, Western blot analysis, RNA immunoprecipitation, and RNA stability assays were conducted to elucidate the underlying molecular mechanisms. The Hepatocellular Carcinoma Database (HCCDB) was utilized for gene expression analysis of CYP1B1 and METTL14.</p><p><strong>Results: </strong>Upregulated CYP1B1 in HCC inhibits ferroptosis and promotes cell proliferation by mediating GPX4, without significantly affecting HCC cell migration or apoptosis. METTL14-mediated m⁶A modification negatively regulates CYP1B1 expression in HCC. Specifically, METTL14 (downregulated in HCC) catalyzes m6A methylation of CYP1B1 mRNA, reducing its stability, while YTHDF3 binds to CYP1B1 mRNA to decrease its expression.</p><p><strong>Discussion: </strong>These findings established a functional link between drug metabolism, m⁶A epigenetics, and iron-dependent cell death in HCC, highlighting CYP1B1 and its upstream m⁶A machinery as potential targets for developing precision therapies that enhance ferroptosis sensitivity in HCC. The clinical relevance of the identified molecular mechanisms necessitates additional in-depth exploration.</p><p><strong>Conclusion: </strong>CYP1B1 promotes HCC cell proliferation by regulating GPX4-mediated ferroptosis resistance, while METTL14-mediated m6A modification serves as a key negative regulatory mechanism for CYP1B1. Targeting CYP1B1 as a therapeutic strategy holds substantial promise for future drug development in HCC.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":1.8000,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"m6A Modified-CYP1B1 Promotes HCC Cell Proliferation by Inhibiting Ferroptosis.\",\"authors\":\"Wenwen Huang, Haihong Hu, Sheng Cai, Xiaoli Zheng, Su Zeng\",\"doi\":\"10.2174/0113892002387502250714112923\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>CYP1B1, a crucial drug-metabolizing enzyme, metabolizes both endogenous compounds and clinical drugs. The present study investigated the effects of CYP1B1 on the proliferation, migration, apoptosis, and ferroptosis of HCC cells. It further elucidated the regulatory role of m⁶A modification, particularly via the methyltransferase METTL14-in regulating CYP1B1 mRNA stability and translation efficiency.</p><p><strong>Methods: </strong>CCK-8, colony formation, wound healing, and transwell assays were employed to assess the role of CYP1B1 in HCC cell proliferation and migration. Ferroptosis-related assays, Western blot analysis, RNA immunoprecipitation, and RNA stability assays were conducted to elucidate the underlying molecular mechanisms. The Hepatocellular Carcinoma Database (HCCDB) was utilized for gene expression analysis of CYP1B1 and METTL14.</p><p><strong>Results: </strong>Upregulated CYP1B1 in HCC inhibits ferroptosis and promotes cell proliferation by mediating GPX4, without significantly affecting HCC cell migration or apoptosis. METTL14-mediated m⁶A modification negatively regulates CYP1B1 expression in HCC. Specifically, METTL14 (downregulated in HCC) catalyzes m6A methylation of CYP1B1 mRNA, reducing its stability, while YTHDF3 binds to CYP1B1 mRNA to decrease its expression.</p><p><strong>Discussion: </strong>These findings established a functional link between drug metabolism, m⁶A epigenetics, and iron-dependent cell death in HCC, highlighting CYP1B1 and its upstream m⁶A machinery as potential targets for developing precision therapies that enhance ferroptosis sensitivity in HCC. The clinical relevance of the identified molecular mechanisms necessitates additional in-depth exploration.</p><p><strong>Conclusion: </strong>CYP1B1 promotes HCC cell proliferation by regulating GPX4-mediated ferroptosis resistance, while METTL14-mediated m6A modification serves as a key negative regulatory mechanism for CYP1B1. Targeting CYP1B1 as a therapeutic strategy holds substantial promise for future drug development in HCC.</p>\",\"PeriodicalId\":10770,\"journal\":{\"name\":\"Current drug metabolism\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2025-08-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current drug metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0113892002387502250714112923\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current drug metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0113892002387502250714112923","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
m6A Modified-CYP1B1 Promotes HCC Cell Proliferation by Inhibiting Ferroptosis.
Introduction: CYP1B1, a crucial drug-metabolizing enzyme, metabolizes both endogenous compounds and clinical drugs. The present study investigated the effects of CYP1B1 on the proliferation, migration, apoptosis, and ferroptosis of HCC cells. It further elucidated the regulatory role of m⁶A modification, particularly via the methyltransferase METTL14-in regulating CYP1B1 mRNA stability and translation efficiency.
Methods: CCK-8, colony formation, wound healing, and transwell assays were employed to assess the role of CYP1B1 in HCC cell proliferation and migration. Ferroptosis-related assays, Western blot analysis, RNA immunoprecipitation, and RNA stability assays were conducted to elucidate the underlying molecular mechanisms. The Hepatocellular Carcinoma Database (HCCDB) was utilized for gene expression analysis of CYP1B1 and METTL14.
Results: Upregulated CYP1B1 in HCC inhibits ferroptosis and promotes cell proliferation by mediating GPX4, without significantly affecting HCC cell migration or apoptosis. METTL14-mediated m⁶A modification negatively regulates CYP1B1 expression in HCC. Specifically, METTL14 (downregulated in HCC) catalyzes m6A methylation of CYP1B1 mRNA, reducing its stability, while YTHDF3 binds to CYP1B1 mRNA to decrease its expression.
Discussion: These findings established a functional link between drug metabolism, m⁶A epigenetics, and iron-dependent cell death in HCC, highlighting CYP1B1 and its upstream m⁶A machinery as potential targets for developing precision therapies that enhance ferroptosis sensitivity in HCC. The clinical relevance of the identified molecular mechanisms necessitates additional in-depth exploration.
Conclusion: CYP1B1 promotes HCC cell proliferation by regulating GPX4-mediated ferroptosis resistance, while METTL14-mediated m6A modification serves as a key negative regulatory mechanism for CYP1B1. Targeting CYP1B1 as a therapeutic strategy holds substantial promise for future drug development in HCC.
期刊介绍：
Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.
More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.
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