Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

For a long time, apoptosis was considered the sole form of programmed cell death during development, homeostasis and disease, whereas necrosis was regarded as an unregulated and uncontrollable process. Evidence now reveals that necrosis can also occur in a regulated manner. The initiation of programmed necrosis, 'necroptosis', by death receptors (such as tumour necrosis factor receptor 1) requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3), and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes. Necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death.

One of the key challenges in cancer research is how to effectively kill cancer cells while leaving the healthy cells intact. Cancer cells often have defects in cell death executioner mechanisms, which is one of the main reasons for therapy resistance. To enable growth, cancer cells exhibit an increased iron demand compared with normal, non-cancer cells. This iron dependency can make cancer cells more vulnerable to iron-catalyzed necrosis, referred to as ferroptosis. The identification of FDA-approved drugs as ferroptosis inducers creates high expectations for the potential of ferroptosis to be a new promising way to kill therapy-resistant cancers.). This redox cycle is referred to as the Harber-Weiss reaction. In non-enzymatic lipid peroxidation, free radicals, such as hydroxyl radicals (OH $ ), abstract a hydrogen from a polyunsaturated fatty acid (PUFA) forming a carbon-centered phospholipid (PL) radical (PL $ ). PL $ reacts with molecular oxygen (O 2 ), forming a phospholipid peroxyl radical (PLOO $ ). PLOO $ abstracts hydrogen from another PUFA, forming a phospholipid hydroperoxide (PLOOH) and a new PL $ , which can react again with O 2 . In enzymatic lipid peroxidation, lipoxygenases (LOX) catalyze the dioxygenation of PUFAs and generate PLOOH. On the one hand, PLOOH in the presence of ferrous iron (Fe 2+ ) can be decomposed to alkoxyl phospholipid radical (PLO $ ), which by attacking another PUFA promotes further propagation of lipid peroxidation. On the other hand, PLOOH may decompose to 4-hydroxynonenal (4-HNE) or malondialdehyde (MDA), which by crosslinking may inactivate proteins. Peroxidation of PLs and generation of 4-HNE or MDA cause membrane instability and permeabilization, leading to cell death. Glutathione peroxidase 4 (GPX4) possesses a unique capability to reduce reactive PL hydroperoxides to unreactive PL-alcohol (PL-OH), which interrupts the free radical chain reaction and suppresses lipid peroxidation.

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.