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Peer-reviewedCC BY 4.0Cell Communication and Signaling : CCS

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

  • Zian Feng1
  • Zhiheng Xia2
  • Hui Zhang1
  • Chong Fan1
  • Zhenxiao Ma3
  • Mengyao Wang4
  • Ke Gong5
  • Baofa Sun6
  • Shuang Zhang7
  • Yajun Duan1
  • Buchun Zhang1
  • Zequn Yin1,8
8 affiliations
  1. 1Department of Cardiology, Division of Life Sciences and Medicine, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui 230026 China
  2. 2Department of Cardiology, Affiliated Anhui Provincial Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui 230032 China
  3. 3Department of Anesthesiology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui 230026 China
  4. 4Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 China
  5. 5Department of Physiology, Faculty of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei 442000 China
  6. 6State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071 China
  7. 7College of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230601 China
  8. 8Anhui Institute of Cardiovascular Disease, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui 230026 China
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03140-3.

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Cite

BibTeXRIS
BibTeX
@article{feng2026intermittent,
  title = {{Intermittent fasting promotes plaque regression and activates the BMAL1–MERTK efferocytosis axis}},
  author = {Zian Feng and Zhiheng Xia and Hui Zhang and Chong Fan and Zhenxiao Ma and Mengyao Wang and Ke Gong and Baofa Sun and Shuang Zhang and Yajun Duan and Buchun Zhang and Zequn Yin},
  journal = {Cell Communication and Signaling : CCS},
  year = {2026},
  month = aug,
  doi = {10.1186/s12964-026-03140-3},
  url = {https://doi.org/10.1186/s12964-026-03140-3},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Intermittent fasting promotes plaque regression and activates the BMAL1–MERTK efferocytosis axis
AU  - Zian Feng
AU  - Zhiheng Xia
AU  - Hui Zhang
AU  - Chong Fan
AU  - Zhenxiao Ma
AU  - Mengyao Wang
AU  - Ke Gong
AU  - Baofa Sun
AU  - Shuang Zhang
AU  - Yajun Duan
AU  - Buchun Zhang
AU  - Zequn Yin
PY  - 2026
DA  - 2026/08/11
JO  - Cell Communication and Signaling : CCS
DO  - 10.1186/s12964-026-03140-3
UR  - https://doi.org/10.1186/s12964-026-03140-3
AB  - Background: 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.  Methods: 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.  Results: 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.  Conclusions: 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.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03140-3.
SN  - 1478-811X
ER  -