Understanding Endoplasmic Reticulum Stress as a Central Driver of Atherosclerosis

Atherosclerosis (AS) remains a major contributor to cardiovascular disease (CVD) mortality worldwide. Its development involves dysregulated lipid handling, persistent vascular inflammation, and endothelial cell (EC) dysfunction, influenced by genetic, environmental, and lifestyle factors. Increasing evidence highlights a pivotal role of endoplasmic reticulum (ER) stress as a molecular link between lipid dysregulation and inflammatory signaling in AS pathogenesis. ER stress is triggered by modified LDL, oxidized lipids, hyperhomocysteinemia, oxidative stress (OS), and disrupted calcium (Ca2+) homeostasis, leading to activation of the unfolded protein response (UPR). Core UPR mediators—inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6)—initially act to restore ER homeostasis but, when persistently activated, may drive pro-inflammatory cytokine production, apoptosis, and plaque destabilization. The aim of this review is to critically synthesize primary research evidence on ER stress as a mediator of lipid-driven inflammation in ECs, macrophages, and vascular smooth muscle cells (VSMCs), emphasizing disease-stage–specific effects. Current debates include whether macrophage ER stress promotes necrotic core expansion vs. apoptosis-mediated clearance, and whether ER stress in ECs is initially protective or primarily pathogenic. Emerging therapeutic strategies targeting ER stress are summarized, including chemical chaperones, AMPK activators, and natural compounds. We highlight the importance of lipid- and inflammation-specific ER stress modulation, noting limitations such as off-target effects and poor bioavailability that hinder translation. Our goal is to achieve a deeper understanding of the lipid–ER stress–inflammation axis to facilitate the design of therapies that may slow AS progression.