The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages.
Chronic activation of endoplasmic reticulum stress in hepatocytes drives nonalcoholic steatohepatitis (ΝASH) pathogenesis, insulin resistance, fat accumulation, inflammation, fibrogenesis and liver fibrosis through inadequate unfolded protein response, cell death and inflammation.
Mitochondrial dysfunction and oxidative stress drive NASH and liver fibrosis by causing hepatocyte damage, immune cell activation and inflammation.
Cellular stress pathways in hepatocytes also contribute to fibrogenesis independent of NASH.
Intracellular reactive oxygen species generation provokes endoplasmic reticulum stress and autophagy that contribute to the activation of hepatic stellate cells.
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The authors declare no competing interests.
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Sharma, S., Le Guillou, D. & Chen, J.Y. Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis. Nat Rev Gastroenterol Hepatol 20, 662–678 (2023). https://doi.org/10.1038/s41575-023-00832-w