Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS. Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids. Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD. Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54-83.
Keywords: fatty acids; inflammation; metabolism; microbiota; oxidative stress; pro-resolving lipid mediators.