MDM2/Notch-Ferroptosis crosstalk in cancer: metabolic rewiring, immune evasion, and organ-specific metastasis

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a contributor to tumor progression and therapy response. Two of the most widely studied oncogenic regulators, the E3 ubiquitin ligase MDM2 and the Notch receptor family, have been independently reported to modulate ferroptosis through effects on p53/SLC7A11, NUMB/Notch/GPX4, and mitochondrial metabolism. This review surveys the primary experimental evidence for these interactions and evaluates the extent to which MDM2- and Notch-dependent pathways converge on ferroptosis effectors across cancer types. We then examine how the resulting metabolic changes, mitochondrial respiration, lipid peroxidation, cystine/glutathione homeostasis, and iron handling, intersect with tumor immune evasion and with organ-specific metastatic colonization. Throughout, we distinguish mechanistically coupled interactions (demonstrated in a single experimental system) from parallel or correlative observations across disparate systems. We conclude by outlining specific experimental gaps, including the scarcity of matched MDM2 and Notch manipulation data in single-tumor models, the unresolved context dependence of Notch’s pro- and anti-ferroptotic effects, the dual role of ferroptosis in anti-tumor immunity versus immune-cell fitness, and the lack of validated clinical biomarkers. The synthesis is intended as a resource for investigators designing mechanistic studies, rather than as a prescriptive therapeutic framework.