Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets
Abstract In drug development, systematically characterizing a compound’s mechanism of action (MoA), including its direct targets and effector proteins, is crucial yet challenging. Network-based approaches, unlike those focused solely on direct targets, effectively detect a wide range of cellular res...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07886-3 |
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| author | Rina Kunishige Yoshiyuki Noguchi Naomi Okamoto Lei Li Akito Ono Masayuki Murata Fumi Kano |
| author_facet | Rina Kunishige Yoshiyuki Noguchi Naomi Okamoto Lei Li Akito Ono Masayuki Murata Fumi Kano |
| author_sort | Rina Kunishige |
| collection | DOAJ |
| description | Abstract In drug development, systematically characterizing a compound’s mechanism of action (MoA), including its direct targets and effector proteins, is crucial yet challenging. Network-based approaches, unlike those focused solely on direct targets, effectively detect a wide range of cellular responses elicited by compounds. This study applied protein covariation network analysis, leveraging quantitative, morphological, and localization features from immunostained microscopic images, to elucidate the MoA of AX-53802, a novel ferroptosis inducer. From the candidate targets extracted through network analysis, GPX4 was verified as the direct target by validation experiments. Additionally, aggregates involving GPX4, TfR1, and F-actin were observed alongside iron reduction, suggesting a ferroptosis defense mechanism. Furthermore, combination therapies targeting GPX4 and FAK/Src were found to enhance cancer cell death, and MDM2, ezrin, and cortactin were identified as potential ferroptosis inhibitor targets. These findings highlight the effectiveness of network-based approaches in uncovering a compound’s MoA and developing combination therapies for cancer. |
| format | Article |
| id | doaj-art-32a03bde395e4f3f87dc31d6fc56eae6 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-32a03bde395e4f3f87dc31d6fc56eae62025-08-20T01:54:25ZengNature PortfolioCommunications Biology2399-36422025-03-018111610.1038/s42003-025-07886-3Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targetsRina Kunishige0Yoshiyuki Noguchi1Naomi Okamoto2Lei Li3Akito Ono4Masayuki Murata5Fumi Kano6Multimodal Cell Analysis Collaborative Research Cluster, Institute of Science TokyoCellshoot Therapeutics, Inc.Cellshoot Therapeutics, Inc.Cellshoot Therapeutics, Inc.Axcelead Drug Discovery Partners, Inc.Multimodal Cell Analysis Collaborative Research Cluster, Institute of Science TokyoMultimodal Cell Analysis Collaborative Research Cluster, Institute of Science TokyoAbstract In drug development, systematically characterizing a compound’s mechanism of action (MoA), including its direct targets and effector proteins, is crucial yet challenging. Network-based approaches, unlike those focused solely on direct targets, effectively detect a wide range of cellular responses elicited by compounds. This study applied protein covariation network analysis, leveraging quantitative, morphological, and localization features from immunostained microscopic images, to elucidate the MoA of AX-53802, a novel ferroptosis inducer. From the candidate targets extracted through network analysis, GPX4 was verified as the direct target by validation experiments. Additionally, aggregates involving GPX4, TfR1, and F-actin were observed alongside iron reduction, suggesting a ferroptosis defense mechanism. Furthermore, combination therapies targeting GPX4 and FAK/Src were found to enhance cancer cell death, and MDM2, ezrin, and cortactin were identified as potential ferroptosis inhibitor targets. These findings highlight the effectiveness of network-based approaches in uncovering a compound’s MoA and developing combination therapies for cancer.https://doi.org/10.1038/s42003-025-07886-3 |
| spellingShingle | Rina Kunishige Yoshiyuki Noguchi Naomi Okamoto Lei Li Akito Ono Masayuki Murata Fumi Kano Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets Communications Biology |
| title | Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets |
| title_full | Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets |
| title_fullStr | Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets |
| title_full_unstemmed | Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets |
| title_short | Protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets |
| title_sort | protein covariation networks for elucidating ferroptosis inducer mechanisms and potential synergistic drug targets |
| url | https://doi.org/10.1038/s42003-025-07886-3 |
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