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Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF\u2010CD74 in septic cardiomyopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>This study evaluated the impact of CD74 ablation on endotoxaemia\u2010induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca<jats:sup>2+<\/jats:sup> properties were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening\/relengthening, prolonged duration of relengthening and intracellular Ca<jats:sup>2+<\/jats:sup> mishandling) and ultrastructural derangement associated with inflammation, O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down\u2010regulated Skp2, an F\u2010box component of Skp1\/Cullin\/F\u2010box protein\u2010type ubiquitin ligase, while up\u2010regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. <jats:italic>In vitro<\/jats:italic> study revealed that LPS facilitated GFP\u2010LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS\u2010induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5\u2010AzaC ameliorated LPS\u2010induced GFP\u2010LC3B formation and cardiomyocyte contractile dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our data suggested that CD74 ablation protected against LPS\u2010induced cardiac anomalies, O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production, inflammation and apoptosis through suppression of autophagy in a Skp2\u2010SUV39H1\u2010mediated 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