Cross-talk between WNT Signaling and Ferroptosis in Cancer

Abstract Cancer remains one of the most formidable challenges in the medical field in this century, largely because of its poorly understood pathogenesis. Fortunately, recent advancements in the understanding of cancer pathogenesis have helped identify more therapeutic targets for improved treatment outcomes. The WNT signaling pathways are highly conserved cascades that participate in diverse physiologic processes, such as embryonic development, tissue homeostasis, and tissue regeneration. Ferroptosis, a unique iron-dependent form of cell death that is distinct from apoptosis, is driven by lipid peroxidation and excessive reactive oxygen species production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate cross-talk, plays crucial roles in cancer progression and therapeutic resistance, indicating their potential as targets for cancer therapies. This review provides a comprehensive overview of the current understanding of the cross-talk between WNT signaling pathways and ferroptosis in the pathogenesis and progression of cancer, with a specific focus on the regulatory role of the canonical WNT cascade in cancer-related ferroptosis. In addition, we discuss the pharmacologic mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors and ferroptosis inducers with current therapies represents a promising therapeutic strategy for personalized cancer treatment.