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Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell's secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.

 The ER stress mainly includes the accumulation of misfolded and unfolded proteins in lumen and the disorder of Ca²⁺ balance. ROS mediates several critical aspects of the ER stress response. We summarize the latest advances in of the UPR and ER stress in the pathogenesis of pulmonary disease and discuss potential therapeutic strategies aimed at restoring ER proteostasis in pulmonary disease.

Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.