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CYR61 liver-specific knockout mice on a NASH diet showed improved glucose tolerance, decreased liver inflammation, and reduced fibrosis. CYR61 polarized infiltrating monocytes promoting a proinflammatory\/profibrotic phenotype through an IRAK4\/SYK\/NF-\u03baB signaling cascade. In vitro, CYR61 activated a profibrotic program, including PDGFa\/PDGFb expression in macrophages, in an IRAK4\/SYK\/NF-\u03baB\u2013dependent manner. Furthermore, targeted-antibody blockade reduced CYR61-driven signaling in macrophages in vitro and in vivo, reducing fibrotic development. 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