A guide to cell death pathways.

Targeting cuproplasia and cuproptosis in cancer.

Necroptosis refers to a regulated form of cell death induced by a variety of stimuli. Although it has been implicated in the pathogenesis of many diseases, there is evidence to support that necroptosis is not purely a detrimental process. We propose that necroptosis is a "double-edged sword" in terms of physiology and pathology. On the one hand, necroptosis can trigger an uncontrolled inflammatory cascade response, resulting in severe tissue injury, disease chronicity, and even tumor progression. On the other hand, necroptosis functions as a host defense mechanism, exerting antipathogenic and antitumor effects through its powerful pro-inflammatory properties. Moreover, necroptosis plays an important role during both development and regeneration. Misestimation of the multifaceted features of necroptosis may influence the development of therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge of the pathways involved in necroptosis as well as five important steps that determine its occurrence. The dual role of necroptosis in a variety of physiological and pathological conditions is also highlighted. Future studies and the development of therapeutic strategies targeting necroptosis should fully consider the complicated properties of this type of regulated cell death. 

/pdf/the-double-edged-functions-of-necroptosis-11dl798a.pdf

The double-edged functions of necroptosis

Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) is a master regulator of TNFR1 signaling in controlling cell death and survival. While the scaffold of RIPK1 participates in the canonical NF-κB pathway, the activation of RIPK1 kinase promotes not only necroptosis and apoptosis, but also inflammation by mediating the transcriptional induction of inflammatory cytokines. The nuclear translocation of activated RIPK1 has been shown to interact BAF-complex to promote chromatin remodeling and transcription. This review will highlight the proinflammatory role of RIPK1 kinase with focus on human neurodegenerative diseases. We will discuss the possibility of targeting RIPK1 kinase for the treatment of inflammatory pathology in human diseases.

/pdf/targeting-ripk1-kinase-for-modulating-inflammation-in-human-3bb2l5v8.pdf

Targeting RIPK1 kinase for modulating inflammation in human diseases

Lung ischemia-reperfusion injury (LIRI) is associated with many diseases, including primary graft dysfunction after lung transplantation, and has no specific and effective therapies. Necroptosis contributes to the pathogenesis of ischemia-reperfusion injury. Necrostatin-1 (Nec-1), the necroptosis inhibitor targeting RIPK1, has been reported to alleviate ischemia-reperfusion injury in various organs. However, the underlying mechanism of Nec-1 in LIRI remains unclear. In this paper, an in vivo LIRI model was built up by left lung hilar clamping in mice, and an in vitro cold ischemia-reperfusion (CI/R) model using BEAS-2B cells was applied to mimic the lung transplantation setting. We found Nec-1 significantly alleviated ischemia-reperfusion-induced lung injury, cytokine releasing, and necroptosis of epithelial cells in mouse lungs. In vitro, Nec-1 also mitigated CI/R-induced cell death and inflammatory responses in BEAS-2B cells, and these protective effects were achieved by simultaneously inhibiting the formation of necrosome and RIPK1-dependent apoptosis. However, Nec-1 decreased the necrosome number but increased the apoptosis level in lung tissues after ischemia reperfusion. We further clarified that Nec-1 could also attenuate lung injury by promoting neutrophil apoptosis from flow cytometry. In conclusion, Nec-1 alleviated lung ischemia-reperfusion injury by inhibiting necroptosis and apoptosis of epithelial cells and promoting the apoptosis of neutrophils. Thus, Nec-1 could be a promising medication against primary graft dysfunction after lung transplantation.

/pdf/necrostatin-1-alleviates-lung-ischemia-reperfusion-injury-1q82f2g3.pdf

Necrostatin-1 Alleviates Lung Ischemia-Reperfusion Injury via Inhibiting Necroptosis and Apoptosis of Lung Epithelial Cells

Adenosine monophosphate–activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress–induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation. Description Editor’s summary A critical phosphorylation event links the metabolic state of a cell with control of cell death and inflammation. Adenosine monophosphate–dependent protein kinase (AMPK) is a sensor of the nutrient status and energy state of the cell. Zhang et al. found that activated AMPK phosphorylates and inhibits receptor-interacting protein kinase 1 (RIPK1) in nutrient-deprived cells, thus inhibiting cell death and inflammation (see the Perspective by Hardie). Under more prolonged nutrient stress, such inhibition was lost, allowing cell death to ensue. These results also confirm RIPK1’s role in cell death caused by ischemia, thus implicating the AMPK-RIPK1 interaction as a potential therapeutic target. —L. Bryan Ray Protein kinases control a metabolic checkpoint that dictates cell responses to metabolic stress.

Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1

Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation

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Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1

Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation