Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia
Objectives: While ferroptosis induction emerges as a therapeutic strategy for solid tumors, its role in acute myeloid leukemia (AML) remains unexplored. This study aimed to investigate the role of MLN4924 in modulating ferroptosis and its molecular targets in AML.Methods: Transcriptome sequencing an...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Hematology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/16078454.2025.2497041 |
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| author | Jinli Jian Yuancheng Guo Xiao Tang Long Zhao Bei Liu |
| author_facet | Jinli Jian Yuancheng Guo Xiao Tang Long Zhao Bei Liu |
| author_sort | Jinli Jian |
| collection | DOAJ |
| description | Objectives: While ferroptosis induction emerges as a therapeutic strategy for solid tumors, its role in acute myeloid leukemia (AML) remains unexplored. This study aimed to investigate the role of MLN4924 in modulating ferroptosis and its molecular targets in AML.Methods: Transcriptome sequencing and bioinformatics analyses were performed to identify MLN4924 potential targets in ferroptosis. First, ferroptosis-related phenotypic assays were conducted, including assays of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ levels. Second, cell viability assays were carried out with the combination of MLN4924 and ferroptosis inducers (Erastin, Sorafenib). Third, rescue experiments were used the ferroptosis inhibitor Ferrostatin-1 after MLN4924 treatment. In vivo efficacy was evaluated in NOD/SCID mice bearing AML xenografts treated with MLN4924, followed by tumor tissue analysis of GSH and Fe2+ levels, immunohistochemistry (IHC), and Western blotting for SLC7A11/GPX4 axis components.Results: Transcriptome sequencing and bioinformatics analyses identified SLC7A11 and GPX4 as key MLN4924 target genes, both of which are glutathione-related proteins. MLN4924 significantly suppressed SLC7A11 and GPX4 expression, decreased GSH activity, and increased ROS, Fe2+, and MDA levels. Ferroptosis inducers (Erastin, Sorafenib) further enhanced the antileukemic activity of MLN4924, and ferroptosis inhibitor Ferrostatin-1 partially reversed this toxicity. In vivo, MLN4924 reduced tumor burden, accompanied by SLC7A11/GPX4 downregulation and Fe2+ accumulation in xenografts.Conclusion: This study provides the first evidence that MLN4924 triggers ferroptosis in AML by inhibiting the SLC7A11/GPX4 axis. These findings establish MLN4924 as a ferroptosis sensitizer through synergistic effects with ferroptosis inducers, supporting its therapeutic potential in AML. |
| format | Article |
| id | doaj-art-ba3983a8347a425883d1deb8a413f928 |
| institution | DOAJ |
| issn | 1607-8454 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Hematology |
| spelling | doaj-art-ba3983a8347a425883d1deb8a413f9282025-08-20T02:58:54ZengTaylor & Francis GroupHematology1607-84542025-12-0130110.1080/16078454.2025.2497041Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemiaJinli Jian0Yuancheng Guo1Xiao Tang2Long Zhao3Bei Liu4The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of ChinaThe First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of ChinaThe First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of ChinaThe First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of ChinaThe First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of ChinaObjectives: While ferroptosis induction emerges as a therapeutic strategy for solid tumors, its role in acute myeloid leukemia (AML) remains unexplored. This study aimed to investigate the role of MLN4924 in modulating ferroptosis and its molecular targets in AML.Methods: Transcriptome sequencing and bioinformatics analyses were performed to identify MLN4924 potential targets in ferroptosis. First, ferroptosis-related phenotypic assays were conducted, including assays of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ levels. Second, cell viability assays were carried out with the combination of MLN4924 and ferroptosis inducers (Erastin, Sorafenib). Third, rescue experiments were used the ferroptosis inhibitor Ferrostatin-1 after MLN4924 treatment. In vivo efficacy was evaluated in NOD/SCID mice bearing AML xenografts treated with MLN4924, followed by tumor tissue analysis of GSH and Fe2+ levels, immunohistochemistry (IHC), and Western blotting for SLC7A11/GPX4 axis components.Results: Transcriptome sequencing and bioinformatics analyses identified SLC7A11 and GPX4 as key MLN4924 target genes, both of which are glutathione-related proteins. MLN4924 significantly suppressed SLC7A11 and GPX4 expression, decreased GSH activity, and increased ROS, Fe2+, and MDA levels. Ferroptosis inducers (Erastin, Sorafenib) further enhanced the antileukemic activity of MLN4924, and ferroptosis inhibitor Ferrostatin-1 partially reversed this toxicity. In vivo, MLN4924 reduced tumor burden, accompanied by SLC7A11/GPX4 downregulation and Fe2+ accumulation in xenografts.Conclusion: This study provides the first evidence that MLN4924 triggers ferroptosis in AML by inhibiting the SLC7A11/GPX4 axis. These findings establish MLN4924 as a ferroptosis sensitizer through synergistic effects with ferroptosis inducers, supporting its therapeutic potential in AML.https://www.tandfonline.com/doi/10.1080/16078454.2025.2497041MLN4924SLC7A11GPX4ferroptosisacute myeloid leukemia |
| spellingShingle | Jinli Jian Yuancheng Guo Xiao Tang Long Zhao Bei Liu Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia Hematology MLN4924 SLC7A11 GPX4 ferroptosis acute myeloid leukemia |
| title | Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia |
| title_full | Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia |
| title_fullStr | Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia |
| title_full_unstemmed | Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia |
| title_short | Integrated transcriptome profiling and in vitro analysis reveals MLN4924’s role in inducing ferroptosis in acute myeloid leukemia |
| title_sort | integrated transcriptome profiling and in vitro analysis reveals mln4924 s role in inducing ferroptosis in acute myeloid leukemia |
| topic | MLN4924 SLC7A11 GPX4 ferroptosis acute myeloid leukemia |
| url | https://www.tandfonline.com/doi/10.1080/16078454.2025.2497041 |
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