MARCH2, an E3 ubiquitin ligase, protects against myocardial ischemia-reperfusion (I/R) injury by inhibiting pyroptosis through the regulation of the PGAM5/MAVS/NLRP3 axis. In ischemic hearts or mouse hearts following I/R injury, MARCH2 expression is elevated. Genetic ablation of MARCH2 worsens myocardial infarction and cardiac dysfunction. Single-cell RNA sequencing shows that MARCH2 loss activates the NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) acts as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and recruiting NLRP3. MARCH2 interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, reducing PGAM5-MAVS co-condensation and inhibiting NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 ameliorates I/R-induced mouse heart dysfunction. These findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury. MARCH2 is upregulated in ischemic cardiomyopathy (ICM) patients and I/R-challenged mouse hearts. MARCH2 deficiency exacerbates I/R-evoked myocardial damage, as evidenced by infarct size, echocardiographic parameters, and cardiomyocyte mechanics. MARCH2 promotes PGAM5 degradation through K48-linked polyubiquitination, mitigating inflammatory response and pyroptotic cell death. PGAM5-MAVS condensates mediate NLRP3 inflammasome activation, acting as a sponge for PGAM5/MAVS/NLRP3. MARCH2 overexpression reduces I/R injury and preserves cardiac function by inhibiting the PGAM5-MAVS-NLRP3 inflammasome pathway. MARCH2 negatively regulates NF-κB and type I interferon signaling, restraining NLRP3 inflammasome complex assembly and subsequent myocardial pyroptosis. MARCH2 promotes K48-linked polyubiquitination of PGAM5, targeting it for proteasomal degradation. PGAM5 is a serine/threonine-protein phosphatase involved in various biological processes, including immune response and mitochondrial quality control. PGAM5 functions at the converging point of several cell death pathways, including necrotic and ROS-induced cell death. PGAM5 overexpression exacerbates I/R-elicited infarct size, cardiac dysfunction, NLRP3 inflammasome assembly, and myocardial pyroMARCH2, an E3 ubiquitin ligase, protects against myocardial ischemia-reperfusion (I/R) injury by inhibiting pyroptosis through the regulation of the PGAM5/MAVS/NLRP3 axis. In ischemic hearts or mouse hearts following I/R injury, MARCH2 expression is elevated. Genetic ablation of MARCH2 worsens myocardial infarction and cardiac dysfunction. Single-cell RNA sequencing shows that MARCH2 loss activates the NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) acts as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and recruiting NLRP3. MARCH2 interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, reducing PGAM5-MAVS co-condensation and inhibiting NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 ameliorates I/R-induced mouse heart dysfunction. These findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury. MARCH2 is upregulated in ischemic cardiomyopathy (ICM) patients and I/R-challenged mouse hearts. MARCH2 deficiency exacerbates I/R-evoked myocardial damage, as evidenced by infarct size, echocardiographic parameters, and cardiomyocyte mechanics. MARCH2 promotes PGAM5 degradation through K48-linked polyubiquitination, mitigating inflammatory response and pyroptotic cell death. PGAM5-MAVS condensates mediate NLRP3 inflammasome activation, acting as a sponge for PGAM5/MAVS/NLRP3. MARCH2 overexpression reduces I/R injury and preserves cardiac function by inhibiting the PGAM5-MAVS-NLRP3 inflammasome pathway. MARCH2 negatively regulates NF-κB and type I interferon signaling, restraining NLRP3 inflammasome complex assembly and subsequent myocardial pyroptosis. MARCH2 promotes K48-linked polyubiquitination of PGAM5, targeting it for proteasomal degradation. PGAM5 is a serine/threonine-protein phosphatase involved in various biological processes, including immune response and mitochondrial quality control. PGAM5 functions at the converging point of several cell death pathways, including necrotic and ROS-induced cell death. PGAM5 overexpression exacerbates I/R-elicited infarct size, cardiac dysfunction, NLRP3 inflammasome assembly, and myocardial pyro