Cellular signalling · 2026
Erucic acid aggravates cardiac fibrosis after myocardial infarction by CD36-mediated metabolic reprogramming with impaired mitochondrial aerobic oxidation.
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Zhang Meng, Wang Qiongfang, Wang Xiaoyu, Zhang Shengyao, Chen Yutong, Li Shihao, Zhang Ling, Li Letai, Li Guoli, Chen Dilong, Leng Jiajie, Ran Jianhua
Аннотация
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.
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.