Targeting endoplasmic reticulum stress-the responder to lipotoxicity and modulator of non-alcoholic fatty liver diseases.

Introduction: Endoplasmic reticulum (ER) stress occurs with aberrant lipid accumulation and resultant adverse effects and widely exists in nonalcoholic fatty liver disease (NAFLD). It triggers the unfolded protein response (UPR) to restore ER homeostasis and actively participates in NAFLD pathological processes, including hepatic steatosis, inflammation, hepatocyte death, and fibrosis. Such acknowledges drive the discovery of novel NAFLD biomarker and therapeutic targets and the development of ER-stress targeted NAFLD drugs.

Areas Covered: This article discusses and updates the role of ER stress and UPR in NAFLD, the underlying action mechanism, and especially their full participation in NAFLD pathophysiology. It characterizes key molecular targets useful for the prevention and treatment of NAFLD and highlights the recent ER stress-targeted therapeutic strategies for NAFLD.

Expert Opinion: Targeting ER Stress is a valuable and promising strategy for NAFLD treatment, but its smooth translation into clinical application still requires better clarification of the different UPR patterns in diverse NAFLD physiological states. Further understanding of the distinct effects of these various patterns on NAFLD, the thresholds deciding their final impacts, and their actions via non-liver tissues and cells would be of great help to develop a precise and effective therapy for NAFLD. [Figure: see text].