This study investigates the role of IP3R2-mediated Ca²+ release in LPS-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1/GSDMD pathway. The research demonstrates that IP3R2 is crucial for maintaining Ca²+ homeostasis and cell survival. LPS treatment in rats led to cardiac dysfunction, characterized by reduced LVEF, LVFS, and SV, along with increased NLRP3 expression and GSDMD-mediated pyroptosis. The NLRP3 inhibitor MCC950 alleviated LPS-induced pyroptosis, indicating the involvement of the NLRP3 pathway in this process. 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. Furthermore, inhibiting IP3R2 suppressed the NLRP3/Caspase-1/GSDMD pathway, reducing pyroptosis. ER stress and IP3R2-mediated Ca²+ release mutually regulate 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 promotes LPS-induced pyroptosis in cardiomyocytes. The study also shows that ER stress, induced by LPS, enhances IP3R2-mediated Ca²+ release, which in turn exacerbates pyroptosis. Inhibiting ER stress with 4-PBA reduced LPS-induced pyroptosis by targeting the NLRP3/Caspase-1/GSDMD pathway. These findings suggest that IP3R2 is a key player in LPS-induced cardiomyopathy, and its inhibition could be a promising therapeutic strategy for preventing sepsis-induced cardiomyopathy (SIC). The study highlights the complex interplay between IP3R2, ER stress, and the NLRP3/Caspase-1/GSDMD pathway in the pathogenesis of SIC.This study investigates the role of IP3R2-mediated Ca²+ release in LPS-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1/GSDMD pathway. The research demonstrates that IP3R2 is crucial for maintaining Ca²+ homeostasis and cell survival. LPS treatment in rats led to cardiac dysfunction, characterized by reduced LVEF, LVFS, and SV, along with increased NLRP3 expression and GSDMD-mediated pyroptosis. The NLRP3 inhibitor MCC950 alleviated LPS-induced pyroptosis, indicating the involvement of the NLRP3 pathway in this process. 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. Furthermore, inhibiting IP3R2 suppressed the NLRP3/Caspase-1/GSDMD pathway, reducing pyroptosis. ER stress and IP3R2-mediated Ca²+ release mutually regulate 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 promotes LPS-induced pyroptosis in cardiomyocytes. The study also shows that ER stress, induced by LPS, enhances IP3R2-mediated Ca²+ release, which in turn exacerbates pyroptosis. Inhibiting ER stress with 4-PBA reduced LPS-induced pyroptosis by targeting the NLRP3/Caspase-1/GSDMD pathway. These findings suggest that IP3R2 is a key player in LPS-induced cardiomyopathy, and its inhibition could be a promising therapeutic strategy for preventing sepsis-induced cardiomyopathy (SIC). The study highlights the complex interplay between IP3R2, ER stress, and the NLRP3/Caspase-1/GSDMD pathway in the pathogenesis of SIC.