Intermittent fasting promotes plaque regression and activates the BMAL1-MERTK efferocytosis axis

Atherosclerotic cardiovascular disease can progress despite intensive lipid lowering, highlighting the need to identify local mechanisms that remodel established plaques. Intermittent fasting may engage metabolic, circadian, and immune pathways relevant to this process.

We used genome-wide association study structural equation modeling to construct circulatory plaque burden (CPB) and integrated multi-omic data to prioritize candidate pathways. We then tested intermittent fasting in a baseline-controlled Ldlr⁻/⁻ mouse induction-intervention model and evaluated the BMAL1-MERTK efferocytosis axis in macrophages.

Systems-genetic analyses linked systemic atherosclerotic burden to nutrient-response, circadian, and efferocytosis-related pathways. In mice, intermittent fasting reduced plaque size relative to both the ad libitum-fed and week-14 Baseline groups and improved structural features of plaque stability without additional endpoint lipid lowering. Aortic and single-cell analyses prioritized macrophage BMAL1-MERTK signaling. BMAL1 activated the Mertk promoter and occupied the tested promoter region. Mertk re-expression rescued the efferocytosis defect caused by Bmal1 knockdown, whereas MERTK inhibition reversed the benefit of BMAL1 overexpression.

In this mouse model, intermittent fasting promoted remodeling of established atherosclerotic plaques, with macrophage BMAL1-MERTK signaling and efferocytosis identified as contributing mechanisms. These findings provide mechanistic insight and highlight this lifestyle-linked axis as a candidate for future translational investigation alongside established lipid-lowering therapy.