Lytic Cell Death in Metabolic Liver Disease.

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Regulated cell death is intrinsically associated with inflammatory liver disease and is pivotal in governing outcomes of metabolic liver disease. Different types of cell death may coexist in the progression of metabolic liver disease to inflammation, fibrosis, and ultimately cirrhosis. In addition to apoptosis, lytic forms of hepatocellular death, such as necroptosis, pyroptosis and ferroptosis elicit strong inflammatory responses due to cell membrane permeabilization and release of cellular components, contributing to the recruitment of immune cells and activation of hepatic stellate cells. Controlling liver cell death, in turn, emerges with fundamental importance and offers novel opportunities for potential therapeutic intervention. This review summarizes the underlying mechanism of distinct lytic cell death modes and their commonalities, discusses its relevance to metabolic liver diseases of different aetiologies, and acknowledges the limitations of current knowledge in the field. We focus on the role of hepatocyte necroptosis, pyroptosis and ferroptosis in non-alcoholic fatty liver disease, alcohol-associated liver disease and other metabolic liver disorders, as well as potential of translation into human disease.

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