Molecular insights into the role of ferroptosis in cardiorenal cross-talk: Mechanisms and future directions

Abstract

Cardiorenal syndrome (CRS) is a bidirectional relationship shared between the heart and kidneys, both in physiological and pathophysiological perspectives. The metabolic, hemodynamic, and neurohormonal alterations between the heart and kidneys drive this dual-organ damage and are responsible for one of the highest medical concerns around the globe. From a pathophysiological perspective, activation of the renin-angiotensin system, persistent inflammation, oxidative stress, and reactive fibrosis are accountable for the damage to the heart and kidneys. The review focuses on ferroptosis, which is an iron-dependent lipid peroxidation of the plasma membrane that directs the cell towards cell death. The iron-catalyzed lipid peroxides (LOOH), redox imbalance, inactivation of protective machinery systems such as system X_c, glutathione peroxidase (GPX4), increased iron intake by divalent metal transporter 1 (DMT1) and transferrin receptor 1(TFR1), and ferritinophagy promote cellular lipid peroxidation, the fenton reaction, and intracellular Fe⁺² overload that disrupts homeostasis, and the cells are directed towards ferroptotic cell death. Recently, ferroptotic cell death has been described in a multitude of kidney and cardiac disorders, including acute and chronic kidney diseases, myocardial infarction, heart failure, and so on. This review summarizes recent developments in the context of ferroptosis and its involvement in CRS. The molecular pathways and mechanisms, and how modulating the same could be beneficial for dual-organ protection in the heart and kidneys, are discussed.