The article discusses the role of the unfolded protein response (UPR) in liver diseases, focusing on the activation of three key signaling pathways: IRE1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α. These pathways are activated when the endoplasmic reticulum (ER) accumulates misfolded proteins, leading to global mRNA translation attenuation and the selective increase in the translation of specific mRNAs, including those encoding CHOP and ATF4. The UPR aims to increase ER content, expand protein folding capacity, degrade misfolded proteins, and reduce new protein entry into the ER. However, persistent ER stress can lead to apoptosis, potentially mediated through calcium perturbations, reactive oxygen species, and CHOP. The UPR is activated in various liver diseases, including obesity-associated fatty liver disease, viral hepatitis, and alcohol-induced liver injury, all of which are associated with steatosis. The article also explores the potential therapeutic implications of restoring ER homeostasis before ER stress-induced cell death. Additionally, it reviews the UPR's role in nonalcoholic fatty liver disease, protein conformational diseases, cholestasis, chronic viral hepatitis, hyperhomocysteinemia, alcohol-induced liver injury, ischemia-reperfusion injury, acute toxins, and hepatocellular carcinoma.The article discusses the role of the unfolded protein response (UPR) in liver diseases, focusing on the activation of three key signaling pathways: IRE1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α. These pathways are activated when the endoplasmic reticulum (ER) accumulates misfolded proteins, leading to global mRNA translation attenuation and the selective increase in the translation of specific mRNAs, including those encoding CHOP and ATF4. The UPR aims to increase ER content, expand protein folding capacity, degrade misfolded proteins, and reduce new protein entry into the ER. However, persistent ER stress can lead to apoptosis, potentially mediated through calcium perturbations, reactive oxygen species, and CHOP. The UPR is activated in various liver diseases, including obesity-associated fatty liver disease, viral hepatitis, and alcohol-induced liver injury, all of which are associated with steatosis. The article also explores the potential therapeutic implications of restoring ER homeostasis before ER stress-induced cell death. Additionally, it reviews the UPR's role in nonalcoholic fatty liver disease, protein conformational diseases, cholestasis, chronic viral hepatitis, hyperhomocysteinemia, alcohol-induced liver injury, ischemia-reperfusion injury, acute toxins, and hepatocellular carcinoma.