The Role of Endoplasmic Reticulum Stress in Human Pathology Endoplasmic reticulum (ER) stress occurs when the ER's protein-folding capacity is overwhelmed by the demand for properly folded proteins. This stress triggers the unfolded protein response (UPR), a signaling pathway that attempts to restore ER homeostasis. If ER stress persists, the UPR shifts to a terminal state that promotes cell death. Chronic ER stress and defects in UPR signaling are linked to various diseases, including diabetes, neurodegeneration, and cancer. Targeting UPR components is a promising therapeutic strategy for these conditions. The ER is a major site for protein synthesis, folding, and modification. Misfolded proteins in the ER trigger the UPR, which activates three pathways: IRE1α, PERK, and ATF6. These pathways aim to restore ER function by increasing protein-folding capacity, reducing protein synthesis, and enhancing the removal of misfolded proteins. However, if these mechanisms fail, the UPR can lead to apoptosis. In diabetes, ER stress in pancreatic β-cells contributes to insulin deficiency and disease progression. Mutations in genes involved in the UPR, such as PERK and IRE1α, can lead to β-cell dysfunction and diabetes. Similarly, ER stress is implicated in neurodegenerative diseases, where misfolded proteins accumulate and trigger apoptosis. In cancer, ER stress is often present in tumor cells, and the UPR may support tumor growth by promoting survival under stressful conditions. Pharmacological targeting of the UPR is an emerging therapeutic approach. Inhibitors of the UPR, such as PERK and IRE1α inhibitors, are being tested for their potential to treat diseases like diabetes and neurodegeneration. Small molecule chaperones and other UPR modulators may also offer therapeutic benefits by reducing ER stress and promoting cell survival. In conclusion, ER stress is a critical factor in the pathophysiology of many diseases. Understanding the UPR and its role in cell fate under ER stress is essential for developing effective therapies. Targeting components of the UPR offers a promising avenue for treating ER stress-related diseases.The Role of Endoplasmic Reticulum Stress in Human Pathology Endoplasmic reticulum (ER) stress occurs when the ER's protein-folding capacity is overwhelmed by the demand for properly folded proteins. This stress triggers the unfolded protein response (UPR), a signaling pathway that attempts to restore ER homeostasis. If ER stress persists, the UPR shifts to a terminal state that promotes cell death. Chronic ER stress and defects in UPR signaling are linked to various diseases, including diabetes, neurodegeneration, and cancer. Targeting UPR components is a promising therapeutic strategy for these conditions. The ER is a major site for protein synthesis, folding, and modification. Misfolded proteins in the ER trigger the UPR, which activates three pathways: IRE1α, PERK, and ATF6. These pathways aim to restore ER function by increasing protein-folding capacity, reducing protein synthesis, and enhancing the removal of misfolded proteins. However, if these mechanisms fail, the UPR can lead to apoptosis. In diabetes, ER stress in pancreatic β-cells contributes to insulin deficiency and disease progression. Mutations in genes involved in the UPR, such as PERK and IRE1α, can lead to β-cell dysfunction and diabetes. Similarly, ER stress is implicated in neurodegenerative diseases, where misfolded proteins accumulate and trigger apoptosis. In cancer, ER stress is often present in tumor cells, and the UPR may support tumor growth by promoting survival under stressful conditions. Pharmacological targeting of the UPR is an emerging therapeutic approach. Inhibitors of the UPR, such as PERK and IRE1α inhibitors, are being tested for their potential to treat diseases like diabetes and neurodegeneration. Small molecule chaperones and other UPR modulators may also offer therapeutic benefits by reducing ER stress and promoting cell survival. In conclusion, ER stress is a critical factor in the pathophysiology of many diseases. Understanding the UPR and its role in cell fate under ER stress is essential for developing effective therapies. Targeting components of the UPR offers a promising avenue for treating ER stress-related diseases.