Iron and lipid dysregulation as key determinants of ferroptosis in cardiometabolic disease.

Cardiometabolic diseases (CMD) are a major global health threat. Given their multifactorial pathogenesis, understanding the interconnected mechanisms driving disease progression is essential. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron accumulation, lipid peroxidation, and compromised antioxidant defenses, is emerging as a promising target for therapeutic intervention in CMD. Growing evidence underscores the intricate interplay among iron metabolism, redox homeostasis, and lipid metabolism in regulating ferroptosis and CMD. Notably, we propose the concept of an "iron paradox" as an integrative framework to synthesize these observations. Despite representing opposite systemic iron states, both iron deficiency and iron overload can converge on ferroptotic vulnerability by disrupting subcellular iron trafficking, mitochondrial function, lipid remodeling, and antioxidant defense. This framework emphasizes that ferroptosis risk in CMD is not primarily governed directly by absolute iron abundance, but more so the interaction between redox-active iron, PUFA-containing phospholipids and lipid peroxide detoxification systems. We then describe the molecular regulation of ferroptosis, with a focus on disruptions in iron and lipid homeostasis as drivers of lipid peroxidation. The contribution of these cellular changes to CMD pathophysiology is then described. Finally, we summarize preclinical evidence supporting ferroptosis-targeted interventions and outline future directions for translational research and therapeutic innovation.