Lipoprotein‐associated phospholipase A2: The story continues

Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.