Fenofibrate is a fibric acid derivative which exhibits a role of peroxisome proliferator-activated receptor alpha agonist. It is widely utilized in therapy of hyperlipidemia and hypercholesterolemia. Its anticancer function is discovered in recent years. However, the role of fenofibrate in prostate cancer (PCa) is poorly understood. In this study, we investigated the function and mechanism of fenofibrate in PCa cells. Firstly, fenofibrate treated PCa cells showed more apoptosis compared with the control group. Further, we found that fenofibrate induced autophagy but finally blocked its complete flux in PCa cells through regulating AMPK-mTOR pathway. The intermediate metabolite from uncompleted autophagy induced endoplasmic reticulum stress (ER stress) via PERK and IRE1 signalings. In vivo mice model confirmed that fenofibrate inhibited the growth of PCa. This study suggests that fenofibrate is an effective inhibitor of PCa by regulating autophagy and ER stress. (C) 2018 Elsevier Inc. All rights reserved.