The endoplasmic reticulum (ER) plays a crucial role in protein biosynthesis and secretion, and its homeostasis is maintained through the unfolded protein response (UPR). The UPR is an adaptive signaling pathway that responds to ER stress, which can be caused by various factors such as disturbed lipid homeostasis, calcium signaling, oxidative stress, and inflammatory responses. The UPR involves three main components: IRE1α, PERK, and ATF6α, which mediate translational and transcriptional changes to manage protein folding and ER function. Chronic or severe ER stress can lead to apoptosis, and the UPR is implicated in a wide range of diseases, including metabolic disorders, neurodegenerative diseases, inflammatory diseases, and cancer. In diabetes, the UPR is essential for β-cell adaptation to increased protein synthesis, and its dysfunction contributes to β-cell failure. In metabolic syndrome, ER stress exacerbates inflammatory and stress signaling pathways, leading to obesity, insulin resistance, and dyslipidemia. The UPR also plays a role in infectious and inflammatory diseases, where it regulates immune responses and inflammation. In cancer, the UPR is critical for tumor cell growth and survival under hypoxic conditions, and targeting UPR components may be a therapeutic strategy. Despite significant progress, the mechanisms underlying the UPR's role in disease remain largely unknown, and further research is needed to understand its complex functions in various physiological and pathological states.The endoplasmic reticulum (ER) plays a crucial role in protein biosynthesis and secretion, and its homeostasis is maintained through the unfolded protein response (UPR). The UPR is an adaptive signaling pathway that responds to ER stress, which can be caused by various factors such as disturbed lipid homeostasis, calcium signaling, oxidative stress, and inflammatory responses. The UPR involves three main components: IRE1α, PERK, and ATF6α, which mediate translational and transcriptional changes to manage protein folding and ER function. Chronic or severe ER stress can lead to apoptosis, and the UPR is implicated in a wide range of diseases, including metabolic disorders, neurodegenerative diseases, inflammatory diseases, and cancer. In diabetes, the UPR is essential for β-cell adaptation to increased protein synthesis, and its dysfunction contributes to β-cell failure. In metabolic syndrome, ER stress exacerbates inflammatory and stress signaling pathways, leading to obesity, insulin resistance, and dyslipidemia. The UPR also plays a role in infectious and inflammatory diseases, where it regulates immune responses and inflammation. In cancer, the UPR is critical for tumor cell growth and survival under hypoxic conditions, and targeting UPR components may be a therapeutic strategy. Despite significant progress, the mechanisms underlying the UPR's role in disease remain largely unknown, and further research is needed to understand its complex functions in various physiological and pathological states.