Aerobic exercise preconditioning inhibits GSDME-dependent pyroptosis in myocardial ischemia–reperfusion injury through IGFBP2-AKT-PDCD4 signaling

Abstract Restoring blood flow to ischemic myocardium is essential for tissue survival but can itself cause additional injury. Mitochondrial dysfunction and pyroptosis, an inflammatory form of cell death, contribute to this reperfusion injury. Although aerobic exercise protects the heart, how exercise preconditioning engages circulating signals to preserve mitochondria and limit pyroptosis remains unclear. Here we show that insulin-like growth factor-binding protein 2 (IGFBP2) contributes to exercise-induced cardioprotection through IGF-1R/PI3K/AKT signaling and suppression of programmed cell death protein 4 (PDCD4). Human plasma proteomics identified elevated IGFBP2 in individuals with sustained aerobic exercise habits, and experiments in mice and primary cardiomyocytes linked this pathway to mitochondrial preservation and reduced gasdermin E (GSDME)-dependent pyroptosis. A 12-week exercise programme before ischemia–reperfusion improved cardiac function and reduced infarct size, whereas global Igfbp2 knockout or cardiomyocyte-specific Igf1r deficiency largely abolished these benefits. Genetic and pharmacological perturbations supported PDCD4 suppression as a downstream mechanism of IGFBP2 signaling. GSDME deletion reduced cell injury without preventing PDCD4-associated mitochondrial dysfunction, supporting a model in which mitochondrial damage acts upstream of GSDME activation. These findings connect an exercise-responsive circulating factor to mitochondrial protection and downstream control of inflammatory cell death, advancing mechanistic understanding of exercise-induced cardiac resilience. They identify IGFBP2 as an important mediator of this protection, while other exercise-responsive pathways may also contribute. This pathway provides a rationale for investigating approaches to limit reperfusion injury, although its therapeutic relevance requires further validation.