The unfolded protein response (UPR) is a cellular mechanism activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), sensed by the chaperone BiP/GRP78. The UPR involves three pathways: IRE1α, PERK, and ATF6α. IRE1α activates the RNase activity to cleave XBP1 mRNA, producing sXBP1, a potent transcription factor. PERK phosphorylates eIF2α, reducing global translation and selectively increasing ATF4 translation, leading to CHOP expression. ATF6α translocates to the Golgi, where it is cleaved to generate a transcription factor. These pathways aim to restore ER function by increasing protein folding capacity, degrading misfolded proteins, and reducing new protein entry. Prolonged ER stress leads to apoptosis via mechanisms involving calcium, reactive oxygen species, and CHOP. ER stress is implicated in various liver diseases, including non-alcoholic fatty liver disease (NAFLD), viral hepatitis, and alcohol-induced injury. ER stress may contribute to steatosis through lipid homeostasis disruption. Hepatocyte apoptosis is a pathogenic event in liver diseases, potentially linked to unresolved ER stress. Restoring ER homeostasis before cell death could be therapeutic. The UPR is also involved in inflammation, with pathways like NF-κB, JNK, and ROS contributing to inflammatory responses. ER stress is associated with liver injury, with mechanisms involving lipid metabolism, cholesterol, and protein misfolding. In diseases like alpha-1 antitrypsin deficiency, ER stress can lead to liver injury and inflammation. Cholestasis involves bile acid accumulation and ER stress, with CHOP playing a protective role. Chronic viral hepatitis, such as HCV and HBV, activates the UPR, contributing to liver damage. Hyperhomocysteinemia induces ER stress through oxidative stress and lipid accumulation. Alcohol-induced liver injury involves ER stress, with CHOP playing a role in apoptosis. Ischemia-reperfusion injury activates ER stress, with IRE1α involved in the response. Acute toxins like carbon tetrachloride and acetaminophen induce ER stress. Hepatocellular carcinoma is associated with UPR activation, promoting cancer cell survival and resistance to therapy. The UPR is a key player in liver disease pathogenesis, with potential therapeutic targets in ER stress modulation.The unfolded protein response (UPR) is a cellular mechanism activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), sensed by the chaperone BiP/GRP78. The UPR involves three pathways: IRE1α, PERK, and ATF6α. IRE1α activates the RNase activity to cleave XBP1 mRNA, producing sXBP1, a potent transcription factor. PERK phosphorylates eIF2α, reducing global translation and selectively increasing ATF4 translation, leading to CHOP expression. ATF6α translocates to the Golgi, where it is cleaved to generate a transcription factor. These pathways aim to restore ER function by increasing protein folding capacity, degrading misfolded proteins, and reducing new protein entry. Prolonged ER stress leads to apoptosis via mechanisms involving calcium, reactive oxygen species, and CHOP. ER stress is implicated in various liver diseases, including non-alcoholic fatty liver disease (NAFLD), viral hepatitis, and alcohol-induced injury. ER stress may contribute to steatosis through lipid homeostasis disruption. Hepatocyte apoptosis is a pathogenic event in liver diseases, potentially linked to unresolved ER stress. Restoring ER homeostasis before cell death could be therapeutic. The UPR is also involved in inflammation, with pathways like NF-κB, JNK, and ROS contributing to inflammatory responses. ER stress is associated with liver injury, with mechanisms involving lipid metabolism, cholesterol, and protein misfolding. In diseases like alpha-1 antitrypsin deficiency, ER stress can lead to liver injury and inflammation. Cholestasis involves bile acid accumulation and ER stress, with CHOP playing a protective role. Chronic viral hepatitis, such as HCV and HBV, activates the UPR, contributing to liver damage. Hyperhomocysteinemia induces ER stress through oxidative stress and lipid accumulation. Alcohol-induced liver injury involves ER stress, with CHOP playing a role in apoptosis. Ischemia-reperfusion injury activates ER stress, with IRE1α involved in the response. Acute toxins like carbon tetrachloride and acetaminophen induce ER stress. Hepatocellular carcinoma is associated with UPR activation, promoting cancer cell survival and resistance to therapy. The UPR is a key player in liver disease pathogenesis, with potential therapeutic targets in ER stress modulation.