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Abstract Osthole, a coumarin derivative, can increase hepatic peroxisome proliferator-activated receptor α (PPARα) expression and reduce hepatic steatosis and inflammatory response in rats with non-alcoholic steatohepatitis (NASH). In this study, a cell model of NASH was induced with oleic acid (OA)/lipopolysaccharide (LPS) and treated for 36 h with different osthole concentrations. Results showed that intracellular lipid and inflammatory cytokine levels gradually decreased after osthole treatment. These effects, however, were abolished or attenuated after PPARα gene silencing. Accordingly, PPARα gene silencing reversed the osthole-mediated expressions of proteins involved in lipid synthesis and fatty acid oxidation. PPARα gene silencing also abrogated the inhibitory effect of osthole on nuclear factor kappa B p65 protein expression. These findings demonstrate that osthole activates PPARα signaling pathway to inhibit lipid accumulation and inflammatory response in OA/LPS-stimulated hepatocytes. Highlights • Osthole inhibited lipid accumulation and inflammatory response in hepatocytes. • Osthole regulated protein expressions related to lipid metabolism by activating PPARα. • Osthole inhibited NF-κB p65 protein expression by activation of PPARα. [ABSTRACT FROM AUTHOR]