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Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.Cell death can result from the activation of dedicated programmed cell death machineries or disruption of pro-survival mechanisms. This Review describes the different major mechanisms of cell death and discusses recent insights into their relevance to disease.

The clearance of apoptotic cells by professional and non-professional phagocytes — a process termed ‘efferocytosis’ — is essential for the maintenance of tissue homeostasis. Accordingly, defective efferocytosis underlies a growing list of chronic inflammatory diseases. Although much has been learnt about the mechanisms of apoptotic cell recognition and uptake, several key areas remain incompletely understood. This Review focuses on new discoveries related to how phagocytes process the metabolic cargo they receive during apoptotic cell uptake; the links between efferocytosis and the resolution of inflammation in health and disease; and the roles of efferocytosis in host defence. Understanding these aspects of efferocytosis sheds light on key physiological and pathophysiological processes and suggests novel therapeutic strategies for diseases driven by defective efferocytosis and impaired inflammation resolution.Clearing away dead cells — a process known as efferocytosis — is crucial for normal tissue homeostasis and is impaired in several pathological processes. This Review describes new insights into how efferocytes deal with the engulfed dead cell cargo, how efferocytosis supports the resolution of inflammation and how this understanding is informing new therapeutic strategies.

Cell death is critical for the development and homeostasis of almost all multicellular organisms. Moreover, its dysregulation leads to diverse disease states. Historically, apoptosis was thought to be the major regulated cell death pathway, whereas necrosis was considered to be an unregulated form of cell death. However, research in recent decades has uncovered several forms of regulated necrosis that are implicated in degenerative diseases, inflammatory conditions and cancer. The growing insight into these regulated, non-apoptotic cell death pathways has opened new avenues for therapeutic targeting. Here, we describe the regulatory pathways of necroptosis, pyroptosis, parthanatos, ferroptosis, cuproptosis, lysozincrosis and disulfidptosis. We discuss small-molecule inhibitors of the pathways and prospects for future drug discovery. Together, the complex mechanisms governing these pathways offer strategies to develop therapeutics that control non-apoptotic cell death.Several forms of non-apoptotic cell death, such as necroptosis, pyroptosis, parthanatos and ferroptosis, are implicated in degenerative diseases, cancer and inflammation. This article describes the molecular pathways regulating these forms of cell death and gives an update on small-molecule inhibitors being developed to target these pathways.

The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. The recent exciting discoveries defining the molecular machinery involved in efferocytosis have opened many avenues for therapeutic intervention, with several agents now in clinical trials.Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. Here, Mehrotra and Ravichandran discuss the mechanisms of efferocytosis and the role of this physiological process in disease, and assess strategies and agents for therapeutic intervention.

Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death — including apoptosis and necrosis — have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.Pathways of regulated cell death may contribute to the pathogenesis of various kidney diseases. Here, the authors provide an overview of the relationship between necroptosis, pyroptosis, ferroptosis and apoptosis, the evidence supporting a role for these regulated pathways of necrosis in kidney disease, strategies for therapeutic targeting and research needs.

Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis. DFNA5 is related to the caspase-dependent pyroptosis inducer gasdermin D. Here the authors find that DFNA5 is cleaved by caspase 3 and show this cleavage skews cells away from apoptosis into secondary necrosis, a form of cell death characterized by membrane ballooning similar to pyroptosis.

Ruptured and intact plasma membranes are classically considered as hallmarks of necrotic and apoptotic cell death, respectively. As such, apoptosis is usually considered a non-inflammatory process while necrosis triggers in- flammation. Recent studies on necroptosis and pyroptosis, two types of programmed necrosis, revealed that plasma membrane rupture is mediated by MLKL channels during necroptosis but depends on non-selective gasdermin D （GSDMD） pores during pyroptosis. Importantly, the morphology of dying cells executed by MLKL channels can be distinguished from that executed by GSDMD pores. Interestingly, it was found recently that secondary necrosis of apoptotic cells, a previously believed non-regulated form of cell lysis that occurs after apoptosis, can be programmed and executed by plasma membrane pore formation like that of pyroptosis. In addition, pyroptosis is associated with pyroptotic bodies, which have some similarities to apoptotic bodies. Therefore, different cell death programs induce distinctive reshuffling processes of the plasma membrane. Given the fact that the nature of released intracellular contents plays a crucial role in dying/dead cell-induced immunogenicity, not only membrane rupture or integrity but also the nature of plasma membrane breakdown would determine the fate of a cell as well as its ability to elicit an immune response. In this review, we will discuss recent advances in the field of apoptosis, necroptosis and pyroptosis, with an emphasis on the mechanisms underlying plasma membrane changes observed on dying cells and their implication in cell death-elicited immunogenicity.

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.The authors of this Review present the main pathways that regulate apoptosis as well as other signalling pathways that interact with them, highlighting actionable molecular targets for anticancer therapy. They also provide an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents.

Chronic non-healing wounds are a major complication of diabetes, which affects 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair 1 – 3 . Here we reveal that the membrane transporter SLC7A11 acts as a molecular brake on efferocytosis, the process by which dying cells are removed, and that inhibiting SLC7A11 function can accelerate wound healing. Transcriptomics of efferocytic dendritic cells in mouse identified upregulation of several SLC7 gene family members. In further analyses, pharmacological inhibition of SLC7A11, or deletion or knockdown of Slc7a11 using small interfering RNA enhanced efferocytosis in dendritic cells. Slc7a11 was highly expressed in dendritic cells in skin, and single-cell RNA sequencing of inflamed skin showed that Slc7a11 was upregulated in innate immune cells. In a mouse model of excisional skin wounding, inhibition or loss of SLC7A11 expression accelerated healing dynamics and reduced the apoptotic cell load in the wound. Mechanistic studies revealed a link between SLC7A11, glucose homeostasis and diabetes. SLC7A11-deficient dendritic cells were dependent on aerobic glycolysis using glucose derived from glycogen stores for increased efferocytosis; also, transcriptomics of efferocytic SLC7A11-deficient dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetes-prone db/db mice, and targeting SLC7A11 accelerated their wound healing. The faster healing was also linked to the release of the TGFβ family member GDF15 from efferocytic dendritic cells. In sum, SLC7A11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with important implications for wound management in diabetes. Transcriptomic, genetic and pharmacological analysis identifies SLC7A11 as an inhibitor of efferocytosis in dendritic cells, and increased expression of this protein may cause slower wound healing in diabetes.