Atherosclerosis develops as a persistent inflammatory condition that gradually alters the vascular structure and condition, in which the formation of macrophage-derived foam cells plays a central role in disease initiation and progression. Although proprotein convertase subtilisin/kexin type 9 (PCSK9) is widely recognised for its involvement in low-density lipoprotein receptor regulation and systemic lipid homeostasis, growing evidence indicates that PCSK9 also exerts a direct influence on macrophage inflammatory responses and intracellular lipid metabolism. Within atherosclerotic lesions, PCSK9 accelerates foam cell development by promoting oxidised low-density lipoprotein uptake, impairing cholesterol efflux through ABCA1 downregulation and activating key inflammatory pathways, particularly those mediated by TLR4/NF-κB and the NLRP3 inflammasome. This review emphasises recent findings that identify natural bioactive compounds as a novel and biologically relevant approach to counteracting PCSK9-driven inflammatory foam cell formation. Compounds such as salvianolic acid B, curcumin, quercetin, fisetin and myricetin display broad antiatherogenic properties by concurrently regulating macrophage polarisation, limiting scavenger receptor expression, suppressing inflammasome activation and modulating PCSK9 expression or function. In contrast to monoclonal PCSK9 inhibitors, which primarily address lipid lowering, these natural agents offer integrated anti-inflammatory and lipid-modulatory effects at the cellular level. Collectively, the evidence discussed in this review positions PCSK9 modulation by natural compounds as an emerging therapeutic concept that links lipid dysregulation with vascular inflammation. This multitarget strategy may complement current lipid-lowering therapies and support the development of more accessible and inflammation-focused interventions for atherosclerosis.
