2. Academic Validation
  3. FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death

FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death

  • Cell Death Dis. 2025 Jun 2;16(1):426. doi: 10.1038/s41419-025-07754-2.
Byeong-Ju Kim # 1 2,  Sun Mi Hong # 1,  Hyun-Jin Noh 1 2,  Jihye Kim 3,  Su-Yeon Seon 1 2,  Jeong-Eun Lee 1 2,  Da-Hye Jeong 1 2,  Ju-Mi Park 1 2,  Sejeong Park 3,  Sanghoon Lee 3 4,  Jaewoo Kang 3 4,  Dakeun Lee 2 5,  Michael J Morgan 6,  You-Sun Kim 7 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
  • 2 Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, 16499, Republic of Korea.
  • 3 AIGEN Sciences, Seoul, Republic of Korea.
  • 4 Department of Computer Science and Engineering, Korea University, Seoul, 02841, Republic of Korea.
  • 5 Department of Pathology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
  • 6 Department of Natural Sciences, Northeastern State University, Tahlequah, OK, USA.
  • 7 Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. yousunkim@ajou.ac.kr.
  • 8 Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, 16499, Republic of Korea. yousunkim@ajou.ac.kr.
  • # Contributed equally.
PMID: 40456737 DOI: 10.1038/s41419-025-07754-2
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.

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