Shikimic acid, a gut microbiota-derived metabolite, alleviates myocardial ischaemia–reperfusion injury by suppressing ferroptosis
S Li, Y Xu, G MaAbstract
Background
Myocardial ischemia/reperfusion (I/R) injury is still a lack of effective therapeutic drugs. Recently, gut microbiota-derived metabolites have been associated with various cardiovascular diseases. However the specific role of shikimic acid (SA) in the context of I/R injury remains unclear.
Objective
This study aims to investigate the protective role of shikimic acid, a gut microbial metabolite, against myocardial I/R injury and its potential mechanism.
Methods
We established an in vivo mouse model of myocardial I/R and an in vitro hypoxia/reoxygenation (H/R) model using neonatal rat cardiomyocytes (NRCMs). Myocardial tissues underwent untargeted metabolomics to assess metabolic changes. Cardiac function, infarct size, fibrotic area, and reactive oxygen species (ROS) levels were assessed using echocardiography, TTC/Evans blue staining, Masson staining and biochemical assays, respectively. Markers relevant to ferroptosis, including glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and ROS levels were assessed by Western blotting and immunofluorescence.
Results
Metabolomic analysis revealed a significant depletion of SA in I/R-injured myocardial tissues. Exogenous SA supplementation markedly restored cardiac systolic function, including left ventricular ejection fraction and fractional shortening and reduced both infarct size and fibrotic area. Mechanistically, SA treatment suppressed I/R-induced ferroptosis by increased GPX4 expression. These findings were confirmed in vitro, where SA treatment enhanced cardiomyocyte viability and mitigated ROS by maintaining GPX4 and FTH1 expression under H/R conditions.
Conclusion
The gut microbial metabolite SA alleviates myocardial I/R injury by inhibiting ferroptosis through preservation of GPX4 and FTH1. These data suggest that SA may represent a novel therapeutic candidate to alleviate reperfusion injury in ischemia heart disease.Figure 1