One may ask whether induced loss through chemical

One may ask whether induced loss, through chemical or genetic perturbation for example, of an essential cellular factor represents regulated cell death or simple loss of the homeostasis needed for life. For example, deletion of the Mdm2 gene, or inhibition of the MDM2 protein, results in cell death in many cell lines, and in embryonic lethality in mice due to the lack of this essential protein [5], [6], [7], [8], [9]. However, this death and embryonic lethality can be entirely reversed by the simultaneous deletion of the TP53 tumor suppressor gene, which is the major target of MDM2 [6], [8], [10]. Thus, in this case, the idea that normal life requires MDM2, and that loss of MDM2 represents a sabotaging of life's homeostatic machinery is not accurate. Indeed, 680C91 and mice can exist, albeit not as well, without MDM2, as long as they also lack the p53 protein. Similarly, one might wonder if the cell death caused by deletion of an essential metabolic gene represents the loss of an essential factor needed for life (e.g., hexokinases [11]). However, in this case, again, such cells may survive if they are provided with the product of the metabolic enzyme, or an alternative means to satisfy this metabolic need. The important point is that the “normal” requirements for life depend on the network of other cellular and environmental factors present at a given point in time. One might nonetheless suppose that although the cellular factors needed for normal homeostasis are context-dependent, the mechanism of death resulting from the loss of a context-dependent essential factor may not be of interest per se. However, if the cell death mechanism in such a situation reveals the relationship between the missing factor and cellular regulators of its essential function, then this mechanism may indeed be of interest. Moreover, it is possible in some cases to trigger regulated cell death for therapeutic benefit, such as in some cancers. Some pathological processes also act through depletion of essential factors and the resulting cell death process, and inhibition of such death mechanisms may be beneficial. Historically, cell death was divided into three main categories, based on distinctive morphological features: type I cell death, referred to as apoptosis, type II cell death, referred to as cell death involving autophagy, and type III cell death, referred to as necrosis. Regulated cell death was considered synonymous with apoptosis [12], and only more recently was it demonstrated that there are multiple forms of regulated cell death, which are distinct in their molecular mechanisms and morphological characteristics. In contrast to type I and type II cell death, which were considered to be ‘programmed’ and ‘regulated’, necrosis was categorized as an ‘accidental cell death’, and believed to be passive, unregulated, and commonly associated with pathological death caused by exposure to severe insults of a physical, chemical, or mechanical nature that could not be reversed by molecular perturbations [12]. The Nomenclature Committee of Cell Death (NCCD) recommended in 2012 that researchers replace the morphologic classification of cell death with a new classification based on molecular events associated with cell death [13]. This change contributed to a classification of regulated cell death that uses biochemical mechanisms. For instance, even though the notion that death with a necrotic morphology can be molecularly regulated began to emerge in the late 1980s [14], it took two decades until it was widely accepted that ‘necroptosis’ should be classified as a form of regulated cell death [15], [16]. Contributing to this notion were the discoveries of the involvement of molecular mechanisms such as death receptors (e.g., Fas, TNFR1 [17], [18]) and specific kinases (e.g., RIP1, RIP3 [19]) that can be genetically or chemically inhibited to delay or inhibit necroptosis [20]. Necroptosis also has normal physiological functions, such as the modulation of inflammation and the maintenance of adult T-cell homeostasis [15], [21], [22], and may thus be categorized as programmed cell death [23].