This study investigates the role of inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) in lipopolysaccharide (LPS)-induced cardiomyocyte pyroptosis. The researchers established a sepsis model in rats by intraperitoneal injection of LPS and found that LPS increased cardiac dysfunction, as evidenced by echocardiography, histological examination, and increased levels of inflammatory markers. They demonstrated that LPS induced NLRP3 overexpression and GSDMD-mediated pyroptosis in the heart. Treatment with the NLRP3 inhibitor MCC950 alleviated LPS-induced cardiomyocyte pyroptosis. LPS increased ATP-induced intracellular Ca²⁺ release and IP3R2 expression in neonatal rat cardiomyocytes (NRCMs). Inhibiting IP3R2 activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca²⁺ release and pyroptosis by suppressing the NLRP3/Caspase-1/GSDMD pathway. The study also found that ER stress and IP3R2-mediated Ca²⁺ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca²⁺ release, and the mutual regulation of IP3R2 and ER stress further exacerbates LPS-induced pyroptosis in cardiomyocytes. These findings suggest that inhibiting IP3R2 could be a promising therapeutic strategy for sepsis-induced cardiomyopathy.This study investigates the role of inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) in lipopolysaccharide (LPS)-induced cardiomyocyte pyroptosis. The researchers established a sepsis model in rats by intraperitoneal injection of LPS and found that LPS increased cardiac dysfunction, as evidenced by echocardiography, histological examination, and increased levels of inflammatory markers. They demonstrated that LPS induced NLRP3 overexpression and GSDMD-mediated pyroptosis in the heart. Treatment with the NLRP3 inhibitor MCC950 alleviated LPS-induced cardiomyocyte pyroptosis. LPS increased ATP-induced intracellular Ca²⁺ release and IP3R2 expression in neonatal rat cardiomyocytes (NRCMs). Inhibiting IP3R2 activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca²⁺ release and pyroptosis by suppressing the NLRP3/Caspase-1/GSDMD pathway. The study also found that ER stress and IP3R2-mediated Ca²⁺ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca²⁺ release, and the mutual regulation of IP3R2 and ER stress further exacerbates LPS-induced pyroptosis in cardiomyocytes. These findings suggest that inhibiting IP3R2 could be a promising therapeutic strategy for sepsis-induced cardiomyopathy.