To suppress TNF-alpha-induced lipogenesis in sebocytes (associated with acne development) with microRNA-338-3p (miR-338-3p) and to explore the underlying mechanisms. TNF-alpha increased lipid droplet formation in sebocytes which were used as in vitro model of inflammation-induced acne. Flow cytometry and TLC assays validated that miR-338-3p could suppress TNF-alpha-induced lipid droplet formation, down-regulate the expression of PREX2a, and inactivate AKT signaling in sebocytes. In addition, suppression of AKT activity by the PI3 K and AKT inhibitors diminished TNF-alpha-induced lipogenesis. PREX2a siRNA mimics the effects of miR-338-3p on AKT phosphorylation and lipogenesis. PREX2a overexpression consistently restored lipogenesis and AKT phosphorylation attenuated by miR-338-3p. MiR-338-3p suppresses the TNF-alpha-induced lipogenesis in sebocytes by targeting PREX2a and down-regulating PI3K/AKT signaling.