Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling
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.
Authors
- J.G. Li (ORCID: https://orcid.org/0000-0001-5549-1570)
- Zhifei Xu (ORCID: https://orcid.org/0000-0002-1896-097X)
- Ping Huang (ORCID: https://orcid.org/0000-0003-1775-029X)
- Xinyu Tao (ORCID: https://orcid.org/0000-0003-0023-8759)
- Wentong Wu
- Xiu‐Qing Li (ORCID: https://orcid.org/0000-0002-7308-0596)
- Mengting Cheng (ORCID: https://orcid.org/0000-0003-3519-8777)
- Peihua Luo (ORCID: https://orcid.org/0000-0002-6576-2052)
- Feng Jiang (ORCID: https://orcid.org/0000-0002-3525-8752)
- Fei Wang (ORCID: https://orcid.org/0000-0002-2513-502X)
- Zhang Na (ORCID: https://orcid.org/0000-0001-9949-1572)
- Qiaojun He (ORCID: https://orcid.org/0000-0002-0104-6989)
- Nonger Shen (ORCID: https://orcid.org/0009-0002-3657-1123)
Institutions
- Zhejiang Chinese Medical University (CN)
- Zhejiang Cancer Hospital (CN)
- Zhejiang Lab (CN)
- Blood Center of Zhejiang Province (CN)
- Zhejiang Provincial People's Hospital (CN)
- Hangzhou Medical College (CN)
- Hangzhou Cancer Hospital (CN)
- Zhejiang University of Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-04-12
- DOI
- https://doi.org/10.1038/s41420-025-02431-x
- Citations
- 2
- Primary Topic
- Nitric Oxide and Endothelin Effects
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- National Natural Science Foundation of China
- Chinese Medicine Research Program of Zhejiang Province
- Fundamental Research Funds for the Central Universities
- Science and Technology Department of Zhejiang Province