Gomisin N is a physiological substance derived from Schisandra chinensis. In the present study, the in vitro and in vivo effects of gomisin N on endoplasmic reticulum (ER) stress and hepatic steatosis were investigated. We quantified the expression of markers of ER stress, including glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein (C/EBP) homolog protein (CHOP), and X-box-binding protein-1 (XBP-1), and triglyceride (TG) accumulation, in HepG2 cells treated with tunicamycin or palmitate. Tunicamycin treatment in HepG2 cells induced expression of markers of ER stress and increased TG levels; Gomisin N reversed these effects, reducing the expression of markers of ER stress and TG levels. Similar effects were seen following palmitate pretreatment of HepG2 cells. The inhibitory effects of gomisin N were further confirmed in mice injected with tunicamycin. Gomisin N reduced expression of markers of ER stress and decreased TG levels in mouse liver after tunicamycin injection. Furthermore, gomisin N decreased expression of inflammatory and lipogenic genes in palmitate-incubated HepG2 cells. These results suggest that gomisin N inhibits ER stress and ameliorates hepatic steatosis induced by ER stress. Key words gomisin N; endoplasmic reticulum (ER) stress; hepatic steatosis; lipogenesis; inflammationThe endoplasmic reticulum (ER) plays critical roles in the synthesis of secreted and membrane proteins by mediating protein folding, production of lipids and sterols, and the storage of intracellular Ca 2+ . 1) However, pathological factors that disrupt ER homeostasis lead to the accumulation of unfolded protein in the ER lumen, provoking ER stress. Cells usually survive early stress by attenuating protein translation, removing unfolded proteins, and upregulating protein chaperons via the unfolded protein response (UPR).1) However, prolonged ER stress can lead to cell death and cause several diseases including ischemia/reperfusion injury, heart disease, and diabetes. [2][3][4][5] Recent studies show that hepatic ER stress is observed in metabolic diseases such as obesity and diabetes.2-5) ER stress contributes to development of insulin resistance and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). [6][7][8][9]