Dual-Metal Regulation of Cardiac Remodeling: Targeting the LOXL2-Ferroptosis Axis in Metal-Induced Cardiac...

Cardiac remodeling is driven by progressive extracellular matrix stiffening and cardiomyocyte loss. Cardiomyocyte death arising from the progression of fibrosis and ferroptosis, which are regulated by interconnected pathogenic pathways such as lysyl oxidase-like (LOXL), Yes-associated protein (YAP) transcriptional coactivator with PDZ-binding motif (TAZ), and transforming growth factor-beta, leads to cardiac remodeling. However, existing treatments are insufficient to restore heart health. There is mounting evidence that maintaining a healthy balance of metals, particularly copper and iron, can protect the heart from metal-induced cell death, cardiac structural remodeling, and extracellular matrix stiffening. This review examines a therapeutic targeting strategy that emphasises the significance of the Cu-LOXL2-Fe-ferroptosis circuit, a mechanometabolic loop that reinforces the extracellular matrix and oxidative cell death. In this dual-chelation approach, copper modulation inhibits LOXL2-driven extracellular matrix stiffening and profibrotic signaling, while iron chelation suppresses iron-dependent lipid peroxidation and ferroptotic cardiomyocyte death. This combined approach provides a more effective treatment window, interrupting the vicious cycle of tissue damage and cardiomyocyte death. There is preliminary evidence that metal chelators may be able to mitigate ferroptosis and fibrosis, which could lead to possible outcomes.