Endoplasmic reticulum (ER) stress designates a cellular response to the 
accumulation of misfolded proteins, which is related to disease progression in 
the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found 
frequently in medicinal herbs. Although luteolin has been reported to possess 
the therapeutic potential to prevent diverse stage of liver diseases, its role 
in hepatic ER stress has not been established. Thus, the present study aimed to 
determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to 
identify the relevant mechanisms involved in its hepatoprotective effects. In 
hepatocyte-derived cells and primary hepatocytes, luteolin significantly 
decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) 
expression. In addition, luteolin reduced the activation of three canonical 
signaling pathways related to the unfolded protein response, and decreased mRNA 
levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, 
and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 
(SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. 
Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 
2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. 
Deletion of the antioxidant response element in the human SESN2 promoter 
inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a 
critical transcription factor for luteolin-dependent SESN2 expression. In a 
Tm-mediated liver injury model, luteolin decreased serum alanine 
aminotransferase and aspartate aminotransferase activities, prevented 
degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and 
glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin 
may be an effective phytochemical to manage ER stress-related liver injury.