Limonin Attenuates Myocardial Ischemia-Reperfusion Injury via Caspase-3/GSDME Pathway
Overview
Limonin, a natural compound from citrus fruits, significantly reduces myocardial ischemia-reperfusion (I/R) injury by inhibiting pyroptosis and inflammation through the caspase-3/GSDME pathway. Both in vitro and in vivo studies demonstrated that limonin improves cardiac function, decreases myocardial damage, and suppresses inflammatory responses.
Background
Myocardial ischemia-reperfusion injury involves cardiomyocyte death and inflammation, critically impairing cardiac function. Pyroptosis, a pro-inflammatory programmed cell death mediated by caspase-3 cleavage of gasdermin E (GSDME), contributes to this injury by promoting cell membrane rupture and inflammatory factor release. Limonin, a tetracyclic triterpenoid from citrus fruits, has known anti-inflammatory and antioxidant properties but its role in myocardial I/R injury and pyroptosis regulation was previously unclear. This study investigates limonin's protective effects and its mechanism targeting the caspase-3/GSDME pathway in myocardial I/R injury.
Data Highlights
In vitro, limonin inhibited oxygen-glucose deprivation/reoxygenation (OGD/R)-induced pyroptosis and inflammatory factor release in AC16 myocardial cells; these effects were reversed by the caspase-3/GSDME activator triclabendazole. In vivo, limonin pretreatment in C57BL/6 mice subjected to myocardial I/R improved cardiac function parameters, reduced myocardial tissue damage, apoptosis, fibrosis, and inflammatory responses. Mechanistically, limonin suppressed activation of the caspase-3/GSDME pathway, correlating with reduced pyroptosis and inflammation.
Key Findings
Limonin significantly inhibits pyroptosis and inflammatory cytokine release in myocardial cells subjected to simulated I/R injury.
The protective effects of limonin are mediated by suppression of the caspase-3/GSDME pyroptosis pathway.
Activation of caspase-3/GSDME pathway by triclabendazole reverses limonin’s inhibitory effects on pyroptosis and inflammation.
In a mouse myocardial I/R model, limonin pretreatment improves cardiac function and reduces myocardial damage, apoptosis, fibrosis, and inflammation.
Limonin’s inhibition of caspase-3 activation prevents GSDME cleavage, thereby reducing cell membrane pore formation and inflammatory factor release.
Clinical Implications
Limonin represents a promising natural compound for myocardial protection by targeting pyroptosis via the caspase-3/GSDME pathway. Its ability to reduce myocardial cell death and inflammation suggests potential therapeutic application in managing myocardial ischemia-reperfusion injury and improving cardiac outcomes. Further clinical studies are warranted to explore limonin-based interventions in cardiovascular disease.
Conclusion
This study establishes limonin as a novel inhibitor of caspase-3/GSDME-mediated pyroptosis, providing cardioprotection against myocardial I/R injury. These findings offer a theoretical foundation for developing limonin-based therapies to mitigate myocardial damage and inflammation.
References
Limonin Reduces Pyroptosis and Inflammation in Myocardial Ischemia-Reperfusion Mice by Targeting the Caspase-3/GSDME Pathway
Revised American Heart Association statement urges a shift toward plant-based protein and flags ongoing uncertainty in fat and alcohol recommendations.
