Rapamycin reduces ferroptotic stress and shrinks atherosclerotic plaques in mice
The mTOR inhibitor restored macrophage efferocytosis and mitochondrial function while lowering aortic lipid burden in high-fat-fed ApoE-deficient mice.
In a study of ApoE-deficient mice and cultured human cells, researchers found that rapamycin alleviates ferroptotic stress and improves macrophage efferocytosis in atherosclerosis. Investigators treated human THP-1 macrophages with the ferroptosis inducer FIN-56. This compound damaged mitochondrial respiration, suppressed clearance proteins MERTK and MFG-E8, and impaired efferocytosis. Adding rapamycin partially reversed these functional and molecular defects. In ApoE-deficient mice fed a high-fat diet, treatment with 1 mg/kg rapamycin twice weekly for four weeks increased the plaque efferocytosis index from 0.36 to 1.37. Rapamycin also reduced the lipid-positive area across the whole aorta from 25.32% to 12.28%.
Why it matters
Impaired clearance of dying cells accelerates vascular decline and drives necrotic core formation in aging arteries. These findings link mTOR inhibition to the suppression of ferroptotic stress, suggesting a potential route to maintain macrophage function in age-related cardiovascular disease.
Caveats
The animal experiments used a small sample of six mice per group, and the human plaque analysis relied on tissue from only three donors. Further research must determine whether rapamycin confers similar benefits for efferocytosis and plaque stability in human clinical settings.
- Ferrostatin-1
- FIN-56
- Mitotempo
- Rapamycin
- Chronic inflammation
- Mitochondrial dysfunction
- Ferroptosis
- Oxidative stress and ROS signalling
- mTOR signalling
- Apoe
- GPX4
- MERTK
The paper
Rapamycin attenuates ferroptotic stress and improves macrophage efferocytosis in experimental atherosclerosis
Wang Y, He Y, Zhang B et al.
International Immunopharmacology · 2 Oct 2026