Understanding Endoplasmic Reticulum Stress as a Central Driver of AtherosclerosisOA

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(Ca^(2+))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 amediator 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.