α‐Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux

Atherosclerosis, recognized as a prototypical age‐associated vascular disease, is driven by macrophage foam cell formation. Individuals with Parkinson's disease (PD) exhibit an elevated risk for stroke. While α‐synuclein (α‐Syn) is known for its neuronal role in PD, its presence in the circulation and potential vascular effects remain unexplored. Here, we identify α‐Syn as a previously unrecognized circulating factor that promotes atherosclerosis. α‐Syn was detected in human atherosclerotic plaques. Genetic deletion of α‐Syn reduced atherosclerotic lesion size and macrophage lipid accumulation in a mouse model of atherosclerosis induced by overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9). On the contrary, administration of exogenous α‐Syn accelerated atherosclerosis in Apolipoprotein E knockout ( Apoe −/− ) mice. Mechanistically, α‐Syn promoted macrophage foam cell formation by impairing autophagic flux, accompanied by activation of PI3K‐mTOR signaling. Proteomic analysis identified the membrane raft protein flotillin‐1 (FLOT1) as a candidate upstream mediator. Flot1 knockdown reduced α‐Syn internalization, PI3K phosphorylation, autophagy impairment, and lipid accumulation, while pharmacological inhibition of PI3K or mTOR attenuated the effects of α‐Syn. Together, these findings identify a FLOT1‐associated pathway through which extracellular α‐Syn disrupts macrophage autophagy and promotes atherosclerosis.