Significance: Metabolic syndrome (MetS) is associated with a greater risk of diabetes and cardiovascular diseases. It is estimated that this multifactorial condition affects 20%-30% of the world's population. A detailed understanding of MetS mechanisms is crucial for the development of effective prevention strategies and adequate intervention tools that could curb its increasing prevalence and limit its comorbidities, particularly in younger age groups. With advances in basic redox biology, oxidative stress (OxS) involvement in the complex pathophysiology of MetS has become widely accepted. Nevertheless, its clear association with and causative effects on MetS require further elucidation. Recent Advances: Although a better understanding of the causes, risks, and effects of MetS is essential, studies suggest that oxidant/antioxidant imbalance is a key contributor to this condition. OxS is now understood to be a major underlying mechanism for mitochondrial dysfunction, ectopic lipid accumulation, and gut microbiota impairment.
Critical issues: Further studies, particularly in the field of translational research, are clearly required to understand and control the production of reactive oxygen species (ROS) levels, especially in the mitochondria, since the various therapeutic trials conducted to date have not targeted this major ROS-generating system, aimed to delay MetS onset, or prevent its progression.
Future directions: Multiple relevant markers need to be identified to clarify the role of ROS in the etiology of MetS. Future clinical trials should provide important proof of concept for the effectiveness of antioxidants as useful therapeutic approaches to simultaneously counteract mitochondrial OxS, alleviate MetS symptoms, and prevent complications. Antioxid. Redox Signal. 26, 445-461.
Keywords: cardiovascular disease; dyslipidemia; hypertension; insulin resistance; mitochondria; obesity; reactive oxygen species.