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LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported.We sought to establish the role of LKB1 in atherosclerotic foam cell formation.LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet–fed atherosclerosis-prone Ldlr−/− and ApoE−/− mice. LKB1 expression was markedly reduced in human plaques when compared with nonatherosclerotic vessels. Consistently, time-dependent reduction of LKB1 levels occurred in atherosclerotic lesions in western diet–fed Ldlr−/− and ApoE−/− mice. Exposure of macrophages to oxidized low-density lipoprotein downregulated LKB1 in vitro. Furthermore, LKB1 deficiency in macrophages significantly increased the expression of SRA (scavenger receptor A), modified low-density lipoprotein uptake and foam cell formation, all of which were abolished by blocking SRA. Further, we found LKB1 phosphorylates SRA resulting in its lysosome degradation. To further investigate the role of macrophage LKB1 in vivo, ApoE−/−LKB1fl/flLysMcre and ApoE−/−LKB1fl/fl mice were fed with western diet for 16 weeks. Compared with ApoE−/−LKB1fl/fl wild-type control, ApoE−/−LKB1fl/flLysMcre mice developed more atherosclerotic lesions in whole aorta and aortic root area, with markedly increased SRA expression in aortic root lesions.We conclude that macrophage LKB1 reduction caused by oxidized low-density lipoprotein promotes foam cell formation and the progression of atherosclerosis.