Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling
Abstract Sotorasib, the inaugural targeted inhibitor sanctioned for the management of patients afflicted with locally advanced or metastatic non-small cell lung cancer presenting the KRAS G12C mutation, has encountered clinical application constraints due to its potential for cardiac injury as evide...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02431-x |
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| author | Mengting Cheng Wentong Wu Qing Li Xinyu Tao Feng Jiang Jinjin Li Nonger Shen Fei Wang Peihua Luo Qiaojun He Ping huang Zhifei Xu Yiwen Zhang |
| author_facet | Mengting Cheng Wentong Wu Qing Li Xinyu Tao Feng Jiang Jinjin Li Nonger Shen Fei Wang Peihua Luo Qiaojun He Ping huang Zhifei Xu Yiwen Zhang |
| author_sort | Mengting Cheng |
| collection | DOAJ |
| description | Abstract Sotorasib, the inaugural targeted inhibitor sanctioned for the management of patients afflicted with locally advanced or metastatic non-small cell lung cancer presenting the KRAS G12C mutation, has encountered clinical application constraints due to its potential for cardiac injury as evidenced by safety trials. This investigation has elucidated that the heightened expression of neuraminidase-1 (NEU1) constitutes the principal etiology of cardiac damage induced by sotorasib. Mechanistically, sotorasib treatment inhibited the ubiquitinated degradation of NEU1, leading to its elevated expression, which induced downstream AKT signaling pathway inhibition and mitochondrial dysfunction leading to cardiomyocyte apoptosis. Meanwhile, in vivo and in vitro studies showed that D-pantothenic acid (D-PAC) alleviated sotorasib-induced cardiac damage by promoting NEU1 degradation. In conclusion, this study revealed that NEU1 is a key protein in sotorasib cardiotoxicity and that reducing the level of this protein is a critical strategy for the clinical treatment of sotorasib-induced cardiac injury. Schematic representation of a mechanism. |
| format | Article |
| id | doaj-art-c54aa066d3cd4bc7b9a6323884d6a8e5 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-c54aa066d3cd4bc7b9a6323884d6a8e52025-08-20T03:06:48ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111510.1038/s41420-025-02431-xSotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signalingMengting Cheng0Wentong Wu1Qing Li2Xinyu Tao3Feng Jiang4Jinjin Li5Nonger Shen6Fei Wang7Peihua Luo8Qiaojun He9Ping huang10Zhifei Xu11Yiwen Zhang12Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeCenter for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang UniversityClinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityCenter for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang UniversityCenter for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang UniversityClinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeOutpatient Pharmacy, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeCenter for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang UniversityCenter for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang UniversityClinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeCenter for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang UniversityClinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeAbstract Sotorasib, the inaugural targeted inhibitor sanctioned for the management of patients afflicted with locally advanced or metastatic non-small cell lung cancer presenting the KRAS G12C mutation, has encountered clinical application constraints due to its potential for cardiac injury as evidenced by safety trials. This investigation has elucidated that the heightened expression of neuraminidase-1 (NEU1) constitutes the principal etiology of cardiac damage induced by sotorasib. Mechanistically, sotorasib treatment inhibited the ubiquitinated degradation of NEU1, leading to its elevated expression, which induced downstream AKT signaling pathway inhibition and mitochondrial dysfunction leading to cardiomyocyte apoptosis. Meanwhile, in vivo and in vitro studies showed that D-pantothenic acid (D-PAC) alleviated sotorasib-induced cardiac damage by promoting NEU1 degradation. In conclusion, this study revealed that NEU1 is a key protein in sotorasib cardiotoxicity and that reducing the level of this protein is a critical strategy for the clinical treatment of sotorasib-induced cardiac injury. Schematic representation of a mechanism.https://doi.org/10.1038/s41420-025-02431-x |
| spellingShingle | Mengting Cheng Wentong Wu Qing Li Xinyu Tao Feng Jiang Jinjin Li Nonger Shen Fei Wang Peihua Luo Qiaojun He Ping huang Zhifei Xu Yiwen Zhang Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling Cell Death Discovery |
| title | Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling |
| title_full | Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling |
| title_fullStr | Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling |
| title_full_unstemmed | Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling |
| title_short | Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling |
| title_sort | sotorasib impaired degradation of neu1 contributes to cardiac injury by inhibiting akt signaling |
| url | https://doi.org/10.1038/s41420-025-02431-x |
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