Parkin–ACSL4 axis in ferroptosis regulation: a narrative review on therapeutic insights from exercise in aging cardiomyocytes

Figures

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  Fig. 1. Schematic illustration of the molecular pathways regulating ferroptosis in aging cardiomyocytes. During cardiomyocyte aging, impaired AMPK/SIRT1 signaling suppresses the PINK1–Parkin pathway, leading to reduced mitophagy and increased ACSL4 expression. Elevated ACSL4 promotes the incorporation of polyunsaturated fatty acids into membrane phospholipids, enhancing lipid peroxidation and ferroptotic susceptibility. Meanwhile, cytosolic p53 inhibits the cystine/glutamate antiporter (System Xc⁻), thereby limiting cystine uptake and glutathione synthesis. The resulting decrease in GPX4 activity impairs antioxidant defense, promotes lipid peroxide accumulation, and contributes to ferroptosis.

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  Fig. 2. Exercise-induced inhibition of ferroptosis signaling pathways in cardiomyocytes. Aerobic training suppresses ferroptosis in cardiomyocytes by regulating iron metabolism and antioxidant defense systems. Reduced hepcidin expression decreases transferrin receptor (TFR) levels and enhances ferroportin (FPN) activity, limiting intracellular iron accumulation and Fenton reaction–mediated ROS generation. Concurrently, exercise elevates cysteine uptake and glutathione (GSH) synthesis, promoting GPX4 activity that detoxifies lipid peroxides. Together, these adaptations attenuate oxidative stress and lipid peroxidation, thereby protecting cardiomyocytes from ferroptotic cell death.