The role of regulated necrosis in endocrine diseases

Abstract

The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future.

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

“…It has become appreciated recently that necrotic cell death is not always accidental and can instead occur downstream of regulated signaling events. Such types of regulated necrosis are lytic forms of cell death that can drive inflammation and immune responses following plasma membrane rupture and the release of cellular cargo into the extracellular environment [250]. Given previous observations of the molecular mechanisms of β-cell death, ferroptosis and necroptosis appear to be two forms of regulated necrosis with potential relevance to diabetes pathogenesis [252,[259][260][261].…”

“…The presence of certain morphological changes, such as cell shrinking, nuclear condensation, DNA fragmentation, exposure of phosphatidylserine on the plasma membrane, and membrane blebbing, can also be used to identify apoptosis [248,249]. Membrane blebs (also known as apoptotic bodies) encompass cellular content from apoptotic cells for phagocytosis by immune cells, thereby preventing release into the extracellular space and avoiding unwanted immune responses to this physiological process [250]. Thus, while apoptosis likely contributes to the loss of β cells in diabetes, it can also be regarded as a normal physiological process that is immunologically silent [251].…”

“…Examples of this are present throughout the β-cell death literature, and cell death is often called apoptosis despite a lack of direct evidence for apoptosis-specific signatures, such as caspase activation or presence of apoptotic bodies. Adding to this problem, several forms of programed necrosis have been described [250,[276][277][278], so death that results from a regulated signaling event is not necessarily apoptosis.…”

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

“…Ferroptosis can be activated by inhibition of glutathione peroxidase 4 (GPX4) (the membrane repair enzyme) or the glutamate/cystine antiporter (xCT), whereas it can be inhibited by iron chelators, lipophilic antioxidants, polyunsaturated fatty acid phospholipids (PUFA-PLs), and lipid peroxidation inhibitors [ 9 , 10 ]. All these regulated necroses participate in the development of multiple diseases, including cardiocerebrovascular injury [ 11 ], neurological disease [ 12 ], ischemic stroke injury [ 4 , 13 ], digestive diseases [ 14 ], kidney diseases [ 15 – 17 ], liver diseases [ 18 ], endocrine diseases [ 19 ], hypertension [ 20 ], pulmonary disease [ 21 , 22 ], and cancer [ 7 , 23 , 24 ]. Moreover, it has also been implicated in the pathogenesis of corneal diseases.…”

Signature Construction and Molecular Subtype Identification Based on Pyroptosis-Related Genes for Better Prediction of Prognosis in Hepatocellular Carcinoma

“…A recent study demonstrated the critical regulatory role of pyroptosis in the tumor microenvironment (TME), which provides new therapeutic insights for cancer treatment [ 16 ]. Therefore, an in-depth study of pyroptosis may help understand its role in the occurrence and development of cancers including HCC and provide new ideas for the clinical prevention and treatment [ 17 , 18 ].…”