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.

Atherosclerosis (AS) is a key contributor to ischemic heart disease, resulting in significant cardiovascular (CV) morbidity and mortality worldwide. Despite advancements in managing conventional risk factors, including the utilization of statins, recurrent adverse cardiovascular events remain prevalent, emphasizing the need for novel therapeutic strategies. This review explores the critical role of inflammation in the pathogenesis of coronary artery disease (CAD) and highlights potential atheroprotective approaches targeting inflammatory pathways. We discuss the multifaceted interplay between immune responses and AS, detailing the contributions of myeloid cells, T lymphocytes, and various cytokines in plaque formation and instability. Recent research suggests that inflammatory biomarkers, particularly high-sensitivity C-reactive protein (hs-CRP), serve as valuable predictors for CV events. Innovative therapies, including interleukin (IL)-1 and IL-6 inhibitors, colchicine, and statins, exhibit promise in mitigating inflammation-associated cardiovascular risks. Furthermore, emerging agents such as sodium-glucose transport protein 2 (SGLT2) inhibitors and natural compounds like Brazilian green propolis may enhance treatment outcomes. This review aims to highlight the central role of inflammation in CAD management and to outline future research directions focused on novel anti-inflammatory therapies that may improve clinical outcomes in patients at risk for cardiovascular events.