Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC
Abstract Acquired resistance remains a bottleneck for molecular‐targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib‐resistant models, increa...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202401399 |
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| author | Yuanxiang Lu Jinghan Zhu Yuxin Zhang Wentao Li Yixiao Xiong Yunhui Fan Yang Wu Jianping Zhao Changzhen Shang Huifang Liang Wanguang Zhang |
| author_facet | Yuanxiang Lu Jinghan Zhu Yuxin Zhang Wentao Li Yixiao Xiong Yunhui Fan Yang Wu Jianping Zhao Changzhen Shang Huifang Liang Wanguang Zhang |
| author_sort | Yuanxiang Lu |
| collection | DOAJ |
| description | Abstract Acquired resistance remains a bottleneck for molecular‐targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib‐resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S‐adenosylmethionine (SAM), for N6‐methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3‐PCK2‐SAM‐m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2‐DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC. |
| format | Article |
| id | doaj-art-91e77e00a6db4ef28e427cdc440e4547 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-91e77e00a6db4ef28e427cdc440e45472025-08-20T01:59:00ZengWileyAdvanced Science2198-38442024-12-011146n/an/a10.1002/advs.202401399Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCCYuanxiang Lu0Jinghan Zhu1Yuxin Zhang2Wentao Li3Yixiao Xiong4Yunhui Fan5Yang Wu6Jianping Zhao7Changzhen Shang8Huifang Liang9Wanguang Zhang10Hepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Breast Surgery Zhengzhou University People's Hospital Henan Provincial People's Hospital Zhengzhou 450003 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Hepatobiliary Surgery Sun Yat‐sen Memorial Hospital of Sun Yat‐sen University Yanjiang West Road Guangzhou 510120 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaAbstract Acquired resistance remains a bottleneck for molecular‐targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib‐resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S‐adenosylmethionine (SAM), for N6‐methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3‐PCK2‐SAM‐m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2‐DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC.https://doi.org/10.1002/advs.202401399glycolysisIGF2BP3 lactylationlenvatinib resistancePCK2serine metabolism |
| spellingShingle | Yuanxiang Lu Jinghan Zhu Yuxin Zhang Wentao Li Yixiao Xiong Yunhui Fan Yang Wu Jianping Zhao Changzhen Shang Huifang Liang Wanguang Zhang Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC Advanced Science glycolysis IGF2BP3 lactylation lenvatinib resistance PCK2 serine metabolism |
| title | Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC |
| title_full | Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC |
| title_fullStr | Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC |
| title_full_unstemmed | Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC |
| title_short | Lactylation‐Driven IGF2BP3‐Mediated Serine Metabolism Reprogramming and RNA m6A—Modification Promotes Lenvatinib Resistance in HCC |
| title_sort | lactylation driven igf2bp3 mediated serine metabolism reprogramming and rna m6a modification promotes lenvatinib resistance in hcc |
| topic | glycolysis IGF2BP3 lactylation lenvatinib resistance PCK2 serine metabolism |
| url | https://doi.org/10.1002/advs.202401399 |
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