Exploring the molecular interactions between ferroptosis and the Wnt/β-catenin signaling pathway: Implications for cancer and disease therapy

Abstract

Ferroptosis, a regulated form of cell death dependent on iron and marked by lipid peroxidation, is increasingly recognized for its role in a wide array of diseases, including cancers, neurodegenerative disorders, and tissue damage. This review examines the dynamic interaction between ferroptosis and the Wnt/β-catenin signaling pathway, focusing on how Wnt surface receptors, ligands, antagonists, and associated components influence the regulation of ferroptosis. Key elements such as Frizzled receptors, Wnt ligands, and antagonists like DKK1 are shown to affect ferroptosis by altering oxidative stress, lipid dynamics, and iron metabolism. A central aspect of this interaction is the role of the destruction complex, particularly GSK-3β, which regulates ferroptosis through its upstream modulation by the AKT pathway and downstream control over NRF2, GPX4, and SLC7A11. Furthermore, the involvement of β-catenin/TCF transcription factors in the regulation of ferroptosis emphasizes the significance of this pathway in promoting cell survival and resisting ferroptosis, particularly in various cancers. Multiple cancers, including colorectal, breast, ovarian, and lung cancers, are affected by disruptions in the Wnt/ferroptosis axis, where enhanced Wnt signaling helps cancer cells evade ferroptosis and develop resistance to treatments. Beyond cancer, this axis also plays a crucial role in neurodegenerative diseases and conditions like myocardial infarction. Additionally, natural compounds have shown potential in modulating the Wnt/ferroptosis pathway, offering promising therapeutic approaches for a variety of diseases. This review highlights the molecular mechanisms of the Wnt/ferroptosis axis, paving the way for innovative treatment options in cancer and other diseases.