Ferroptosis and Notch Signaling Drive Tumor Progression and Therapeutic Vulnerability
Keywords:
Ferroptosis, Notch, Lipid Peroxidation, Cancer Therapeutic Targets, Metabolic Reprogramming, Immunogenic Cell Death (ICD), Iron metabolism, Precision oncologyAbstract
Ferroptosis is an iron-dependent form of regulated cell death characterized by unchecked lipid peroxidation and redox imbalance, which makes cancer cells vulnerable. The Notch signaling pathway is involved in cell survival, proliferation, differentiation, and helps cells adapt to metabolic and oxidative stress. Notch signaling intersects with ferroptosis through specific mechanisms: it modulates iron homeostasis by altering iron transport and storage proteins, influences lipid metabolism by regulating enzymes that modify membrane phospholipids, and affects antioxidant defenses by controlling the expression of genes such as SLC7A11 that regulate glutathione levels. As a result, Notch activity can sensitize cells to ferroptotic death by encouraging iron accumulation and lipid remodeling or confer resistance by increasing antioxidant capacity and reducing oxidative damage. In cancer, alterations in both ferroptosis and Notch signaling contribute to tumor initiation, progression, metastasis, and therapeutic resistance, in part through mechanistic interactions.
Recent studies report a link between ferroptosis and Notch signaling in several tumor types. However, this relationship likely varies by cancer type and experiment. Studying how these pathways connect could reveal new therapeutic targets, particularly in cancers that rely upon Notch-dependent metabolic programs or resist ferroptosis. Future work should address practical concerns. Selecting appropriate cellular targets, refining delivery methods, and understanding the tumor microenvironment will be important before demonstrating clinical benefits. Ultimately, more targeted ways to exploit the ferroptosis-Notch link may expand precision oncology tools. However, this remains under investigation and has not yet been approved as a therapy.
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