Targeting STIM1 attenuates LPS-induced cardiac dysfunction by reshaping calcium homeostasis and mitochondrial function

Dysregulated calcium homeostasis and mitochondrial impairment are critical factors in the pathogenesis of sepsis-induced cardiomyopathy (SICM). STIM1 is crucial for maintaining calcium homeostasis. However, whether improving STIM1-mediated calcium handling can alleviate SICM remains unknown. This study aims to clarify the mechanism and the role of STIM1 in SICM. In this study, we first established a rat model of sepsis induced by LPS and clarified that the upregulation of STIM1 protein is associated with sepsis-induced cardiomyopathy (SICM). Myocardial-specific knockdown of STIM1 significantly improved cardiac function in septic rats. Moreover, using the calcium influx inhibitor BTP2, we elucidated that BTP2 could alleviate LPS-induced cardiomyopathy by improving calcium handling and mitochondrial function. Subsequently, we treated cardiomyocytes with LPS to explore the mechanism by which STIM1 promotes SICM. The results demonstrated that STIM1 amplifies store-operated calcium entry, triggering concomitant cytosolic and mitochondrial calcium overload. This induces Drp1-dependent mitochondrial fragmentation and dysfunction, resulting in elevated ROS production and subsequent activation of the NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes, ultimately leading to LPS-induced cardiomyopathy. In conclusion, this study indicate that STIM1 promotes calcium overload, thereby facilitating mitochondrial dysfunction and ultimately resulting in pyroptosis. Targeting STIM1 may thus represent a promising therapeutic strategy for SICM. • STIM1 was overexpressed in the cardiomyocytes of septic rats. • STIM1 knockdown attenuated myocardial injury in septic rats. • STIM1 knockdown ameliorated mitochondrial calcium overload and mitochondrial dysfunction. • STIM1 knockdown ameliorated mitochondrial dysfunction and inhibited cardiomyocyte pyroptosis in septic rats.