The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding, and stress signaling. ER stress, characterized by the accumulation of unfolded or misfolded proteins, triggers the unfolded-protein response (UPR), which aims to restore ER homeostasis. Recent studies have revealed that the UPR can initiate inflammation through various signaling pathways, including the production of reactive oxygen species (ROS), calcium release, nuclear factor-κB (NF-κB) activation, and mitogen-activated protein kinase (MAPK) activation. This cross-talk between ER stress and inflammation is particularly significant in specialized cells such as hepatocytes, β-cells, adipocytes, macrophages, and oligodendrocytes, where metabolic and immune functions are critical. Prolonged activation of the UPR and inflammation can lead to the development of diseases such as obesity, type 2 diabetes, atherosclerosis, and neurodegenerative disorders. Therapeutic interventions that modulate the UPR and inflammatory response, such as chemical chaperones and phosphatase inhibitors, show promise in improving disease outcomes. Understanding the complex interactions between ER stress and inflammation is essential for developing effective treatments for these conditions.The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding, and stress signaling. ER stress, characterized by the accumulation of unfolded or misfolded proteins, triggers the unfolded-protein response (UPR), which aims to restore ER homeostasis. Recent studies have revealed that the UPR can initiate inflammation through various signaling pathways, including the production of reactive oxygen species (ROS), calcium release, nuclear factor-κB (NF-κB) activation, and mitogen-activated protein kinase (MAPK) activation. This cross-talk between ER stress and inflammation is particularly significant in specialized cells such as hepatocytes, β-cells, adipocytes, macrophages, and oligodendrocytes, where metabolic and immune functions are critical. Prolonged activation of the UPR and inflammation can lead to the development of diseases such as obesity, type 2 diabetes, atherosclerosis, and neurodegenerative disorders. Therapeutic interventions that modulate the UPR and inflammatory response, such as chemical chaperones and phosphatase inhibitors, show promise in improving disease outcomes. Understanding the complex interactions between ER stress and inflammation is essential for developing effective treatments for these conditions.