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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-\u03baB 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.<\/jats:p>","DOI":"10.1038\/s41419-025-07754-2","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T08:41:48Z","timestamp":1748853708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death"],"prefix":"10.1038","volume":"16","author":[{"given":"Byeong-Ju","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Mi","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Jin","family":"Noh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Yeon","family":"Seon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Eun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Hye","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Mi","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sejeong","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewoo","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakeun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6687-1269","authenticated-orcid":false,"given":"Michael J.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6488-3015","authenticated-orcid":false,"given":"You-Sun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"7754_CR1","doi-asserted-by":"publisher","first-page":"1159743","DOI":"10.3389\/fimmu.2023.1159743","volume":"14","author":"W Li","year":"2023","unstructured":"Li W, Yuan J. Targeting RIPK1 kinase for modulating inflammation in human diseases. Front Immunol. 2023;14:1159743.","journal-title":"Front Immunol"},{"key":"7754_CR2","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/nrm3683","volume":"14","author":"D Ofengeim","year":"2013","unstructured":"Ofengeim D, Yuan J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol. 2013;14:727\u201336.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"7754_CR3","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.tcb.2019.12.009","volume":"30","author":"T Delanghe","year":"2020","unstructured":"Delanghe T, Dondelinger Y, Bertrand MJM. RIPK1 Kinase-Dependent Death: A Symphony of Phosphorylation Events. 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