Endoplasmic reticulum (ER) stress is a critical factor in cardiovascular disease, triggering various modes of cell death through the unfolded protein response (UPR) pathway. The ER maintains cellular homeostasis by ensuring proper protein folding and calcium homeostasis. When ER stress occurs, it activates the UPR, which initially helps restore ER function but can lead to cell death if prolonged. ER stress is associated with several cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. The UPR involves three main pathways: IRE1α, PERK, and ATF6, each contributing to different cellular responses, including autophagy, apoptosis, ferroptosis, pyroptosis, and necroptosis. These processes are crucial in the pathogenesis of cardiovascular diseases and can be targeted for therapeutic intervention. Modulating ER stress through pharmacological agents or molecular chaperones shows promise in treating cardiovascular diseases by reducing cell death and restoring ER homeostasis. Further research is needed to identify reliable biomarkers for ER stress and to develop targeted therapies for cardiovascular diseases.Endoplasmic reticulum (ER) stress is a critical factor in cardiovascular disease, triggering various modes of cell death through the unfolded protein response (UPR) pathway. The ER maintains cellular homeostasis by ensuring proper protein folding and calcium homeostasis. When ER stress occurs, it activates the UPR, which initially helps restore ER function but can lead to cell death if prolonged. ER stress is associated with several cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. The UPR involves three main pathways: IRE1α, PERK, and ATF6, each contributing to different cellular responses, including autophagy, apoptosis, ferroptosis, pyroptosis, and necroptosis. These processes are crucial in the pathogenesis of cardiovascular diseases and can be targeted for therapeutic intervention. Modulating ER stress through pharmacological agents or molecular chaperones shows promise in treating cardiovascular diseases by reducing cell death and restoring ER homeostasis. Further research is needed to identify reliable biomarkers for ER stress and to develop targeted therapies for cardiovascular diseases.