Apomorphine is a novel necroptosis inhibitor targeting mixed lineage kinase domain-like protein oligomerization
- PMID: 41083456
- PMCID: PMC12518639
- DOI: 10.1038/s41420-025-02763-8
Apomorphine is a novel necroptosis inhibitor targeting mixed lineage kinase domain-like protein oligomerization
Abstract
Necroptosis, a form of programmed cell death, has emerged as a promising therapeutic target. Although several RIPK1 inhibitors have demonstrated favorable safety profiles in clinical trials, clinical translation of necroptosis-targeted therapies remains limited by modest efficacy, limited specificity, and species-specific activity of compounds such as necrosulfonamide (NSA). To resolve these challenges, this study identified a potential necroptosis inhibitor from a clinical drug library. Apomorphine (APO), a non-addictive morphine derivative used to treat Parkinson's disease, was found to inhibit necroptosis by sterically blocking key residues involved in mixed lineage kinase domain-like protein (MLKL) activation and oligomerization, as confirmed by nuclear magnetic resonance analysis. APO is redox sensitive and prone to auto-oxidation. The oxidized form of APO (Ox-APO) showed stronger binding to MLKL than the reduced form of APO (Re-APO), as demonstrated by surface plasmon resonance analysis. Ox-APO significantly ameliorated tissue damage in two murine necroptosis models: dextran sulfate sodium (DSS)-induced colitis and acetaminophen (APAP)-induced liver injury. Collectively, these data highlight the therapeutic potential of APO as a necroptosis-specific inhibitor in necroptosis-related diseases in both humans and mice.
© 2025. The Author(s).
Conflict of interest statement
Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: All methods were performed in accordance with relevant guidelines and regulations. C57BL/6 and BALB/c mice were used following procedures approved by the Institutional Animal Care and Use Committee (IACUC) of the Yonsei Laboratory Animal Research Center (YLARC, 2018-0024). MLKL–/– C57BL/6 mice were used following procedures approved by the IACUC of the Laboratory Animal Research Center (LARC) of Ajou University Medical Center (2023-0053). No human participants were involved in this study; therefore, informed consent was not required.
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