Role of ER Stress in Xenobiotic-Induced Liver Diseases and Hepatotoxicity

Abstract

The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic-induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic-related liver diseases.

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“… 1 The ER plays a crucial role in protein quality control and supporting cellular activities. 2 , 3 Disruption of ER homeostasis due to physiological or pathological stimuli leads to the accumulation of misfolded and unfolded proteins, initiating endoplasm ic reticulum stress (ERS) and triggering the unfolded protein response (UPR). 4 In the short term, the UPR serves as an adaptive response, enhancing the cell's capacity to handle ERS and restore ER homeostasis through protein processing, thereby promoting cell survival.…”

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