The Pathophysiological Interrelationship Between Metabolic Dysfunction-Associated Steatotic Liver Disease and...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent multisystem disorder and is strongly associated with increased cardiovascular risk. Cardiovascular diseases represent the leading cause of mortality in this population. As the hepatic manifestation of systemic metabolic dysfunction, MASLD is initiated by excess lipid accumulation driven by increased dietary fatty acid intake and accelerated de novo lipogenesis. This triglyceride overload induces lipotoxicity, triggering hepatocellular injury, immune activation, and mitochondrial dysfunction. Excessive mitochondrial reactive oxygen species (ROS) generation acts as a critical second hit, promoting inflammatory cytokine production and disease progression. Beyond lipid dysregulation, impaired hepatic insulin signaling leads to hyperglycemia and compensatory hyperinsulinemia, further stimulating lipogenesis and reinforcing a self-perpetuating metabolic cycle. Persistent ROS production overwhelms antioxidant defenses and depletes hepatic glutathione (GSH), resulting in systemic redox imbalance. These disturbances extend beyond the liver, contributing to atherogenic dyslipidemia and chronic inflammation. In parallel, gut dysbiosis and increased intestinal permeability amplify immune activation. Reduced circulating GSH further weakens systemic antioxidant capacity; oxidative stress may represent a central mechanistic link between MASLD and CVD. In concert with metabolic and inflammatory mediators, ROS disrupt pathways governing vascular and myocardial homeostasis, leading to coronary atherosclerosis, microvascular dysfunction, left ventricular remodeling, hypertrophy, and impaired relaxation. Clinically, this translates into an increased burden of coronary artery disease and heart failure, particularly heart failure with preserved ejection fraction. Given this integrated pathophysiology, early identification of subclinical cardiovascular involvement is essential. We highlight emerging biomarkers, advocate for multidisciplinary screening strategies, and discuss integrated pharmacological approaches targeting shared metabolic pathways. Recognizing MASLD as a cardiovascular risk amplifier is critical for improving risk stratification and enabling the development of effective, co-targeted therapeutic strategies.