Erucic acid aggravates cardiac fibrosis after myocardial infarction by CD36-mediated metabolic reprogramming with impaired mitochondrial aerobic oxidation

  • Cell Signal. 2026 Oct:146:112636. doi: 10.1016/j.cellsig.2026.112636.
Meng Zhang  1 ,  Qiongfang Wang  1 ,  Xiaoyu Wang  1 ,  Shengyao Zhang  1 ,  Yutong Chen  2 ,  Shihao Li  2 ,  Ling Zhang  2 ,  Letai Li  2 ,  Guoli Li  3 ,  Dilong Chen  4 ,  Jiajie Leng  5 ,  Jianhua Ran  6
Affiliations
  • 1. Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College of Chongqing Medical University, Chongqing, China.
  • 2. Chongqing Medical University, Chongqing, China.
  • 3. Natural Drug Intervention in Aging Key Laboratory of Chongqing Education Commission of China Chongqing Three Gorges Medical College, Chongqing, China.
  • 4. Laboratory of Stem Cells and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing Three Gorges Medical College, Chongqing 404120, China; NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing Institute for Food and Drug Control, Chongqing 401120, China. Electronic address: [email protected].
  • 5. Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 6. Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College of Chongqing Medical University, Chongqing, China; Western Institute of Digital-Intelligent Medicine, Chongqing 401329, China. Electronic address: [email protected].
PMID: 42251941 DOI: 10.1016/j.cellsig.2026.112636
Abstract

Background: Post-myocardial infarction (MI) cardiac fibrosis is a key driver of heart failure, with dysregulated cardiac metabolism playing a central role. The specific impact of circulating fatty acid metabolites on mitochondrial function and fibrotic remodeling remains unclear. Erucic acid, a very-long-chain fatty acid found in certain edible oils, has a historical association with cardiac lipidosis, yet its causal role and mechanism in post-MI fibrosis are unknown.

Methods: We employed an integrative, two-stage strategy. First, a hypothesis-free two-sample Mendelian Randomization (MR) analysis was performed using genome-wide association study (GWAS) data for 1400 serum metabolites and MI (FinnGen consortium) to identify causal risk metabolites. Second, the top-ranked metabolite, erucic acid, was functionally validated in vivo and in vitro. A murine MI model with graded dietary erucic acid supplementation was used to assess cardiac function, fibrosis, oxidative stress, mitochondrial ultrastructure, and energy metabolism. RNA-seq was performed to elucidate global pathway alterations. Complementary in vitro studies in TGF-β-stimulated HL-1 cardiomyocytes and in vivo AAV9-mediated cardiomyocyte-specific CD36 overexpression rescue experiments were conducted to dissect the molecular mechanism involving the CD36 lipid metabolism axis.

Results: MR analysis identified erucic acid as a putative causal risk metabolite for MI. In mice, erucic acid levels increased post-MI, and dietary supplementation dose-dependently exacerbated cardiac dysfunction, fibrosis, oxidative stress, and mitochondrial damage. High-dose erucic acid induced a severe metabolic shift, characterized by suppressed mitochondrial Oxidative Phosphorylation and enhanced glycolysis. In vitro, erucic acid suppressed the CD36 pathway and downstream lipid-handling Enzymes, leading to aggravated lipid peroxidation (increased 4-HNE/rH2X, decreased SOD2). Crucially, in vitro CD36 overexpression rescued these detrimental metabolic and lipotoxic effects. Furthermore, in vivo cardiomyocyte-specific CD36 overexpression via AAV9-cTNT significantly attenuated erucic acid-induced cardiac fibrosis, mitochondrial damage, lipid peroxidation, and the glycolytic shift, firmly establishing CD36 as the central mediator.

Conclusion: This study establishes erucic acid as a causal dietary metabolite that aggravates post-MI cardiac fibrosis. Its pathogenic mechanism involves the disruption of the cardioprotective CD36 lipid metabolism pathway, leading to mitochondrial dysfunction, lipotoxicity, and a detrimental bioenergetic shift. These findings highlight erucic acid and the CD36 axis as potential targets for risk stratification and dietary intervention following MI.

Keywords
CD36; Cardiac fibrosis; Erucic acid; Lipid metabolism; Mitochondrial dysfunction; Myocardial infarction.
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