Atherosclerotic Cell Fates: A Single-Cell View of ER Stress

The role of endoplasmic reticulum (ER) stress in atherosclerosis has long been recognized, but whether it acts as a uniform pathological signal across all cell types has remained unclear. With the advancement of single-cell sequencing technology (scRNA-seq), we can analyze this problem at the resolution of a single cell subpopulation. In this review, we have synthesized the recent evidence from single-cell studies and proposed the "cell type-specific differential response" mode. We believe that endoplasmic reticulum stress does not universally have a pro-atherosclerotic effect. On the contrary, it shows a differential pattern in different atherosclerotic-related cell subpopulations. For example, endoplasmic reticulum stress is activated in monocytes but inhibited in certain macrophage subsets and endothelial cell subsets and dynamically regulated during phenotypic transitions in smooth muscle cells. We explored the underlying mechanisms of this heterogeneity, its impact on plaque progression, and the theoretical basis of subpopulation targeted treatment strategies. Ultimately, we concluded that recognizing the cellular heterogeneity of endoplasmic reticulum stress is the foundation for understanding and precisely intervening in atherosclerotic diseases.