The Coming Decade of Cell Death Research: Five Riddles

Abstract

Active cell death, in its many forms, is a fundamental biological process. Studies over the past several decades have explored the functions and consequences of cellular demise and elucidated several of the key cell death pathways. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.

Figure 1.

Publications on cell death by decade. Results of Pubmed Searches using the terms “apoptosis, necroptosis, pyroptosis, ferroptosis” for each time period shown, divided by total Pubmed publications for that time period. The values are undoubtedly an underestimate.

Figure 2.

Apoptosis The mitochondrial and death receptor pathways of apoptosis are illustrated. Roles for the engagement of caspase-8 and apoptosis are shown in Figure 3.

Figure 3.

Necroptosis Death receptors, TLRs (that engage TRIF), and ZBP1 bind directly or via RIPK1 to activate RIPK3 and, in turn, MLKL, to execute necroptosis. RIPK3 activation is antagonized by the enzymatic activity of the FADD-caspase-8-c-FLIP complex.

Figure 4.

Pyroptosis Several NLRs and AIM2, when activated, directly or indirectly (via ASC) bind to and activate caspase-1, which cleaves GSDMD to effect pyroptosis, and also processes the cytokines IL-1b and IL-18. Caspase-4, caspase-5, and caspase-11 are directly activated by cytosolic LPS and cleave GSDMD, but not the cytokines.

Figure 5.

Ferroptosis The Fenton reaction causes peroxidation of poly-unsaturated fatty acids (PUFA), which in turn catalyze further lipid oxidation in the presence of O₂, disrupting membranes (and generating additional toxic derivatives), leading to ferroptosis. The lipid peroxidase, GPX4, neutralizes oxidized lipids, but requires glutathione (GSH) for recycling. Disruption of GSH synthesis (by cysteine/cystine deprivation or inhibition of the System Xc⁻ transporter) or recycling (requiring NADPH), or inhibition of GPX4 induces ferroptosis in some cells. Ferroptosis is inhibited by sequestration of free iron, inhibition of PUFA synthesis (by ACSL4), or scavenging of reactive oxygen species. Ferroptosis is also inhibited by glutamine deprivation, perhaps due to reduction of PUFA synthesis.