FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death
Abstract Receptor-interacting serine/threonine kinase 1 (RIPK1) is a pivotal protein controlling cell death and inflammation. RIPK1 is an attractive therapeutic target, given that the inhibition of RIPK1 kinase activity has been shown to be effective in animal models of human diseases such as autoim...
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| Format: | Article |
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07754-2 |
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| author | Byeong-Ju Kim Sun Mi Hong Hyun-Jin Noh Jihye Kim Su-Yeon Seon Jeong-Eun Lee Da-Hye Jeong Ju-Mi Park Sejeong Park Sanghoon Lee Jaewoo Kang Dakeun Lee Michael J. Morgan You-Sun Kim |
| author_facet | Byeong-Ju Kim Sun Mi Hong Hyun-Jin Noh Jihye Kim Su-Yeon Seon Jeong-Eun Lee Da-Hye Jeong Ju-Mi Park Sejeong Park Sanghoon Lee Jaewoo Kang Dakeun Lee Michael J. Morgan You-Sun Kim |
| author_sort | Byeong-Ju Kim |
| collection | DOAJ |
| description | Abstract Receptor-interacting serine/threonine kinase 1 (RIPK1) is a pivotal protein controlling cell death and inflammation. RIPK1 is an attractive therapeutic target, given that the inhibition of RIPK1 kinase activity has been shown to be effective in animal models of human diseases such as autoimmune and neurodegenerative diseases. Here, we screened a collection of drugs with structural similarity to necrostatin-1 (Nec-1), an inhibitor of RIPK1, to assess their abilities to regulate RIPK1-mediated immunogenic cell death. Through this small-scale screening of drugs from ongoing clinical trials and FDA-approved drugs, we discovered that the drug phensuximide could prevent necroptosis by targeting RIPK1 kinase activity. Importantly, phensuximide, which has already been approved by the FDA for the treatment of epilepsy, effectively prevents the kinase activity of RIPK1 without affecting the NF-κB and MAPK pathways. The potency of phensuximide is that it protects against both LPS- and TNF-induced systemic inflammatory response syndrome (SIRS), which are sepsis models involving RIPK1 kinase activity. Our findings suggest that phensuximide may serve as a promising strategy for targeting RIPK1-mediated diseases. |
| format | Article |
| id | doaj-art-e7b757f61a004f81903d4afc45904b09 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e7b757f61a004f81903d4afc45904b092025-08-20T02:30:59ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111510.1038/s41419-025-07754-2FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell deathByeong-Ju Kim0Sun Mi Hong1Hyun-Jin Noh2Jihye Kim3Su-Yeon Seon4Jeong-Eun Lee5Da-Hye Jeong6Ju-Mi Park7Sejeong Park8Sanghoon Lee9Jaewoo Kang10Dakeun Lee11Michael J. Morgan12You-Sun Kim13Department of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineAIGEN SciencesDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineAIGEN SciencesAIGEN SciencesAIGEN SciencesDepartment of Biomedical Sciences, Graduate School of Ajou UniversityDepartment of Natural Sciences, Northeastern State UniversityDepartment of Biochemistry, Ajou University School of MedicineAbstract Receptor-interacting serine/threonine kinase 1 (RIPK1) is a pivotal protein controlling cell death and inflammation. RIPK1 is an attractive therapeutic target, given that the inhibition of RIPK1 kinase activity has been shown to be effective in animal models of human diseases such as autoimmune and neurodegenerative diseases. Here, we screened a collection of drugs with structural similarity to necrostatin-1 (Nec-1), an inhibitor of RIPK1, to assess their abilities to regulate RIPK1-mediated immunogenic cell death. Through this small-scale screening of drugs from ongoing clinical trials and FDA-approved drugs, we discovered that the drug phensuximide could prevent necroptosis by targeting RIPK1 kinase activity. Importantly, phensuximide, which has already been approved by the FDA for the treatment of epilepsy, effectively prevents the kinase activity of RIPK1 without affecting the NF-κB and MAPK pathways. The potency of phensuximide is that it protects against both LPS- and TNF-induced systemic inflammatory response syndrome (SIRS), which are sepsis models involving RIPK1 kinase activity. Our findings suggest that phensuximide may serve as a promising strategy for targeting RIPK1-mediated diseases.https://doi.org/10.1038/s41419-025-07754-2 |
| spellingShingle | Byeong-Ju Kim Sun Mi Hong Hyun-Jin Noh Jihye Kim Su-Yeon Seon Jeong-Eun Lee Da-Hye Jeong Ju-Mi Park Sejeong Park Sanghoon Lee Jaewoo Kang Dakeun Lee Michael J. Morgan You-Sun Kim FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death Cell Death and Disease |
| title | FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death |
| title_full | FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death |
| title_fullStr | FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death |
| title_full_unstemmed | FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death |
| title_short | FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death |
| title_sort | fda approved phensuximide inhibits ripk1 dependent immunogenic cell death |
| url | https://doi.org/10.1038/s41419-025-07754-2 |
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