Apoptosis, necroptosis, and pyroptosis in health and disease

Regulated cell death (RCD) plays important roles in health and diseases. The molecular mechanisms underlying several major forms of RCD including apoptosis, necroptosis, and pyroptosis have been well defined. They are triggered by distinct cell death stimuli, operate through separate intracellular machinery, and exert different physiological impacts. These forms of cell death are also intricately interconnected. The roles of these cell death modalities in normal physiology and pathophysiology have been extensively studied. Resistance to apoptosis underlies tumorigenesis and failure of cancer therapy, whereas dysregulated necroptosis and pyroptosis are implicated in diverse pathologies ranging from infectious diseases, acute and chronic inflammation, and cancer etiology and progression. The discovery of key players in RCD pathways provides ample molecular targets for drug developments for treating a broad spectrum of diseases. Apoptosis is regarded as the major form of RCD during animal development and the maintenance of homeostasis. Caspase-dependent apoptosis is estimated to account for about 90% of billions of cell death events in homeostasis. Apoptosis has been a major focus of drug discovery for many years, resulting in the approval of the BCL-2 inhibitor ABT-199 (also known as venclexta and venetoclax) by the Food and Drug Administration for treating CLL (chronic lymphocytic leukemia) and SLL (small lymphocytic lymphoma) in 2016, and many drug candidates targeting apoptosis are in clinical studies. Necroptosis and pyroptosis are lytic form of RCD triggered by infections with pathogens and in response to inflammatory stimuli. Necroptotic and pyroptotic cells release cellular contents known as damage-associated molecular patterns as well as intracellular pathogens in infected cells and associated products known as pathogen-associated molecular patterns which lead to further inflammation. Understanding of the molecular mechanisms underlying necroptosis and pyroptosis has attracted resurgent research interests and some key regulators and their functional roles have been identified and defined in recent years. Because of implications of necroptosis and pyroptosis in diverse human diseases, the development of agents that block or activate necroptosis and pyroptosis has gained intense interest aimed at treating different diseases ranging from inflammatory maladies, infectious diseases to cancer. This chapter succinctly summarizes the key molecular features of apoptosis, necroptosis, and pyroptosis, their dysregulation in human diseases, and major small molecule inhibitors and biologics that modulate these forms of cell death for therapeutic applications.