For Better or Worse: The Impact of Necrotic Cell Death Modalities

Cellular stress, infection, and inflammation lead to various forms of cell death. Depending on the stimulus, cell type, and cellular conditions, different modes of regulated cell death might be engaged. These include apoptosis, necroptosis, and pyroptosis, which are driven by genetically programmed mechanisms, and ferroptosis, a type of metabolic cell death. The outcome of these distinct cell death modalities is the activation of specific pore-forming mechanisms: caspase-3-mediated cleavage of gasdermin E in secondary necrosis following apoptosis (also classified as pyroptosis), RIPK3-mediated phosphorylation of MLKL in necroptosis, and caspase-1/11/4/5-mediated cleavage of GSDMD during pyroptosis. In the case of ferroptosis, a metabolic cell death modality driven by imbalances in iron, lipid, and redox metabolism, the plasma membrane also becomes permeabilized due to oxidative modifications of acyl chains in phospholipids. On top of the pore-forming mechanisms, NINJ1 detects cellular swelling ("oncosis") and triggers a massive plasma membrane rupture as a final stage of the cellular cataclysm, releasing large molecules and intracellular contents. Understanding the mechanisms of regulated necrotic cell death through signaling pathways or by disrupting metabolic networks offers tangible targeting strategies to enhance or reduce cell death processes and associated subroutines in various diseases, including cancer, ischemia/reperfusion conditions, inflammation, and degenerative diseases. Besides the molecular biology, we will concentrate this chapter on the effects of necroptosis, pyroptosis, and ferroptosis in cancer and inflammatory pathologies in the brain, intestine, and skin.