Cardiovascular–kidney–metabolic syndrome and targeted therapeutic strategies

Ferroptosis, an iron-dependent form of regulated cell death, characterized by iron accumulation and lipid peroxidation, is increasingly recognized as a key contributor to the pathophysiology of cardiovascular–kidney–metabolic syndrome (CKMS). This paper elucidates the core mechanisms of ferroptosis, including iron metabolism dysregulation, glutathione peroxidase 4 (GPX4) inactivation, and the excessive peroxidation of polyunsaturated fatty acids. We emphasize its organ-specific actions within CKMS: exacerbating myocardial ischemia-reperfusion injury and atherosclerosis in the cardiovascular system, promoting proximal tubular injury and fibrosis in the kidneys, and worsening insulin resistance and chronic inflammation in metabolic disorders. Consequently, targeting ferroptosis has emerged as a highly promising therapeutic strategy. Potential intervention approaches include iron chelators, GPX4 activators, lipid peroxidation inhibitors, and modulation of key transcription factors such as Nrf2 and p53. These approaches involve agents such as ferrostatin-1, clinically approved drugs, and active components of herbal medicines. This review emphasizes ferroptosis as a pivotal mechanistic link and therapeutic target within CKMS, underscoring the urgent need for in-depth research into stage-specific and organ-specific mechanisms, which will lay the groundwork for future drug development.