omega-Hydroxyundec-9-enoic acid (omega-HUA), a hydroxyl unsaturated fatty acid derivative, is involved in the antifungal activity of wild rice (Oryza officinalis). Here, we investigated the anti-cancer activity of omega-HUA on a non-small cell lung cancer (NSCLC) cell line. omega-HUA increased apoptosis and induced cleavages of caspase-6, caspase-9, and poly (ADP-ribose) polymerase (PARP). omega-HUA treatment significantly induced endoplasmic reticulum (ER) stress response. Suppression of CHOP expression and inhibiting ER stress by 4-phenylbutyrate (4-PBA) significantly attenuated the omega-HUA treatment-induced activation of caspase-6, caspase-9, and PARP, and subsequent apoptotic cell death, indicating a role for ER stress in omega-HUA-induced apoptosis. In addition, cells subjected to omega-HUA exhibited significantly increased quantity of reactive oxygen species (ROS), and the ROS scavenger N-acetyl-L-cysteine (NAC) inhibited omega-HUA-induced apoptotic cell death and ER stress signals, indicating a role for ROS in ER stress-mediated apoptosis in omega-HUA-treated cells. Taken together, these results suggest that sequential ROS generation and ER stress activation are critical in omega-HUA treatment-induced apoptosis and that omega-HUA represents a promising candidate for NSCLC treatment. (C) 2014 Elsevier Inc. All rights reserved.