2. Academic Validation
  3. Melatonin alleviates atherosclerosis by inhibiting pro-inflammatory differentiation of macrophages via regulating Sirt3-Drp1 mediated mitochondrial fission

Melatonin alleviates atherosclerosis by inhibiting pro-inflammatory differentiation of macrophages via regulating Sirt3-Drp1 mediated mitochondrial fission

  • Int Immunopharmacol. 2026 Jan 15:169:116019. doi: 10.1016/j.intimp.2025.116019.
Run Dai 1,  Min-Ming Zheng 2,  Ya-Ni Shi 3,  Ming-Hao Luo 4,  Yu Wang 5,  Hua-Wei Wang 3,  Dan-Qing Yu 6,  Qing-Wei Chen 3,  Ling Lin 7,  Jing-Wei Zhou 8,  Ze-da-Zhong Su 9
Affiliations

Affiliations

  • 1 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
  • 2 Department of Ophthalmology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of General Practice, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Cardiovascular Medicine, Cardiovascular Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Department of Cardiology, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China.
  • 6 Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 7 Department of Geriatric Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China. Electronic address: [email protected].
  • 8 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. Electronic address: [email protected].
  • 9 Department of Geriatric Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China; Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Department of General Practice, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 41389666 DOI: 10.1016/j.intimp.2025.116019
Abstract

Background: Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis.

Methods: The apoE-/- mice were fed a 16-week high-fat diet (HFD). 16 weeks were spent on melatonin therapy. After using 3-TYP to suppress SIRT3 function, we were able to measure the vascular tissue's biochemical, inflammatory, and mitochondrial fission characteristics as well as the shape of atherosclerotic plaque. RAW264.7 cells were stimulated by oxidized low-density lipoprotein (oxLDL), pretreated with or without 3-TYP or Melatonin.

Results: The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of SIRT3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, SIRT3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated SIRT3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the Other hand, melatonin's inhibitory effects on Drp1 expression and mitochondrial fission were lessened by SIRT3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL.

Conclusion: Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin's suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients.

Keywords

Atherosclerosis; Inflammation; Macrophage; Melatonin; Mitochondrial fission; Sirt3-Drp1 pathway.

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