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While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol\u2010induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin\u2010related antimicrobial peptide (CRAMP) on inflammasome activation in ALD. CRAMP knockout (Camp<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) and wild\u2010type (WT) mice were subjected to binge\u2010on\u2010chronic alcohol feeding and synthetic CRAMP peptide was administered. Serum\/plasma and hepatic tissue samples from human subjects with alcohol use disorder and\/or alcoholic hepatitis were analyzed. CRAMP deficiency exacerbated ALD with enhanced inflammasome activation as shown by elevated serum interleukin (IL)\u20101\u03b2 levels. Although Camp<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice had comparable serum endotoxin levels compared to WT mice after alcohol feeding, hepatic lipopolysaccharide (LPS) binding protein (LBP) and cluster of differentiation (CD) 14 were increased. Serum levels of uric acid (UA), a Signal 2 molecule in inflammasome activation, were positively correlated with serum levels of IL\u20101\u03b2 in alcohol use disorder patients with ALD and were increased in Camp<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice fed alcohol. In vitro<\/jats:italic> studies showed that CRAMP peptide inhibited LPS binding to macrophages and inflammasome activation stimulated by a combination of LPS and UA. Synthetic CRAMP peptide administration decreased serum UA and IL\u20101\u03b2 concentrations and rescued the liver from alcohol\u2010induced damage in both WT and Camp<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. In summary, CRAMP exhibited a protective role against binge\u2010on\u2010chronic alcohol\u2010induced liver damage via regulation of inflammasome activation by decreasing LPS binding and UA production. CRAMP administration may represent a novel strategy for treating ALD. \u00a9 2020 The Pathological Society of Great Britain and Ireland. 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