Key result
Shikimic acid restores cardiac function and reduces myocardial infarct size by suppressing ferroptosis in mice.
Why the study?
Myocardial ischemia/reperfusion injury lacks effective therapeutic drugs, and although gut microbiota-derived metabolites have been associated with cardiovascular diseases, the specific role of shikimic acid in ischemia/reperfusion injury remained unclear.
Does exogenous shikimic acid supplementation alleviate myocardial ischemia/reperfusion injury and suppress ferroptosis in preclinical mouse and cardiomyocyte models?
Does exogenous shikimic acid supplementation alleviate myocardial ischemia/reperfusion injury and suppress ferroptosis in preclinical mouse and cardiomyocyte models?
Preclinical findings demonstrate that the gut microbial metabolite shikimic acid protects against myocardial ischemia-reperfusion injury by inhibiting ferroptosis via GPX4 and FTH1 preservation.
Answers are grounded in this paper and cite their sources.
Preclinical data suggest gut metabolites warrant exploration in ischemic heart disease; leaves open translation and efficacy in humans.
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.
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Li et al. (2026) studied Myocardial ischemia/reperfusion (I/R) injury. Shikimic acid (SA) was evaluated on Cardiac systolic function (left ventricular ejection fraction and fractional shortening), infarct size, fibrotic area, and ferroptosis markers (GPX4, FTH1, ROS). Shikimic acid supplementation restored LVEF and fractional shortening, reduced infarct size and fibrosis, and suppressed ferroptosis via GPX4 and FTH1 in murine myocardial I/R injury.
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