Stigmasterol attenuates atherosclerosis by inhibiting inflammatory signaling and foam cell formation

Abstract Foam cells derived from macrophages and smooth muscle cells (SMCs) play a pivotal role in the progression of atherosclerosis. While phytosterols (PS) have demonstrated cholesterol‐lowering and anti‐inflammatory properties, their impact on foam cells remains elusive. Here, we investigated the effects of PS on foam cell formation, inflammatory responses, and lipid metabolism using both single‐cell RNA sequencing (scRNA‐seq) and functional assays. scRNA‐seq of aortic tissue from ApoE −/− mice revealed that PS supplementation reduced proinflammatory macrophages and SMC‐derived intermediate cells. Among the PS components, stigmasterol most effectively attenuated foam cell formation by suppressing oxidized low‐density lipoprotein (ox‐LDL) uptake and enhancing cholesterol efflux. Mechanistically, stigmasterol inhibited the inflammatory CD86 + macrophage polarization by activating the Adenosine Monophosphate‐Activated Protein Kinase (AMPK) pathway and inhibiting the NF‐κB/NLRP3 signaling axis. In SMCs, stigmasterol upregulated ABCA1 and ABCG1 expression, reduced lipid accumulation, and suppressed CD68 expression, thereby limiting trans‐differentiation into macrophage‐like foam cells. In vivo, stigmasterol reduced plaque burden, promoted anti‐inflammatory macrophage polarization, and inhibited SMC‐to‐macrophage transition in ApoE −/− mice. Collectively, these findings uncover a previously underexplored role of stigmasterol in modulating foam cell diversity and inflammation, providing mechanistic insight into the vascular protective effects of dietary PS.