Ferroptosis: key regulatory pathways and their implications in cardiovascular pathophysiology

Cardiovascular diseases (CVDs) remain a leading global health burden, necessitating novel insights into their pathogenesis and therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in CVD progression. This review comprehensively synthesizes current knowledge on the molecular drivers of ferroptosis, including dysregulated iron metabolism, glutathione peroxidase 4 (GPX4) inactivation, and redox imbalance orchestrated by Nrf2, AMPK, and p53. Subcellular organelles such as mitochondria, lysosomes, and the endoplasmic reticulum are highlighted as critical hubs for initiating or amplifying ferroptotic signals through oxidative stress, metabolic dysfunction, and organelle-specific interactions. The role of ferroptosis in major cardiovascular pathologies-atherosclerosis, vascular calcification, heart failure, ischemia-reperfusion injury, and arrhythmias-is systematically explored, emphasizing its contribution to cellular damage, inflammation, and tissue remodeling. Notably, this review incorporates discussions on spatial metabolomics as a powerful analytical tool, highlighting its unique capacity to decipher region-specific metabolic alterations and spatial distribution patterns of key molecules involved in ferroptosis, thereby providing deeper insights into the spatiotemporal dynamics of ferroptotic mechanisms in CVDs. Furthermore, emerging therapeutic strategies targeting ferroptosis, including iron chelators, lipid peroxidation inhibitors, and metabolic modulators (e.g., metformin, trimetazidine), are discussed for their potential to mitigate cardiovascular damage. By bridging molecular mechanisms (enhanced by spatial metabolomics insights) to clinical applications, this review underscores ferroptosis as a promising therapeutic target, advocating for further research to translate these insights into precision interventions for CVD management.