For over four decades, it was believed that two forms of cell death existed: apoptosis, a silent form of programmed cell death; and necrosis, an inflammatory form of non‐programmed cell death. Recent discoveries have provided tremendous insight into the destructive power of regulated necrosis. Apoptosis and regulated necrosis pathways can negatively regulate each other, and this feature may have evolved to counter manipulation of cell death pathways by pathogens. In this chapter we will summarize recent advances in necroptosis, a particular type of regulated necrosis, and outline the distinct pathways to necroptosis induction, the physiological roles of key players and potential therapeutic targets. We will explore the pathophysiological roles for necroptosis in heart attack, multiple sclerosis, atherosclerosis, liver injury, retinal injury, pancreatitis, renal injury, and severe systemic infection and how pathogens evolved to inhibit inflammatory cell death. Finally, we will discuss the fundamental unresolved questions in the necroptotic field, and the recent developments and efforts to target necroptosis in the clinic.
- Death receptors