The therapeutic potential of targeting regulated non-apoptotic cell death

• Published in: Nature reviews. Drug discovery Vol. 22; no. 9; pp. 723 - 742
• Main Authors: Hadian, Kamyar, Stockwell, Brent R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2023; Nature Publishing Group
• Subjects: 631/154; 631/80/82/23; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Cell death; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; Review Article
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/s41573-023-00749-8

Cell death is critical for the development and homeostasis of almost all multicellular organisms. Moreover, its dysregulation leads to diverse disease states. Historically, apoptosis was thought to be the major regulated cell death pathway, whereas necrosis was considered to be an unregulated form of cell death. However, research in recent decades has uncovered several forms of regulated necrosis that are implicated in degenerative diseases, inflammatory conditions and cancer. The growing insight into these regulated, non-apoptotic cell death pathways has opened new avenues for therapeutic targeting. Here, we describe the regulatory pathways of necroptosis, pyroptosis, parthanatos, ferroptosis, cuproptosis, lysozincrosis and disulfidptosis. We discuss small-molecule inhibitors of the pathways and prospects for future drug discovery. Together, the complex mechanisms governing these pathways offer strategies to develop therapeutics that control non-apoptotic cell death. Several forms of non-apoptotic cell death, such as necroptosis, pyroptosis, parthanatos and ferroptosis, are implicated in degenerative diseases, cancer and inflammation. This article describes the molecular pathways regulating these forms of cell death and gives an update on small-molecule inhibitors being developed to target these pathways.