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MDM2/Notch-Ferroptosis crosstalk in cancer: Metabolic rewiring, Immune evasion, and Organ-Specific Metastasis

biochemistry
cell-biology
immunology
oncology
metabolic-sciences

Abstract

Tumor progression is regulated by the crosstalk between the MDM2/Notch signaling pathway and ferroptosis, but the mechanisms of their interactions have not been systematically elucidated. This paper innovatively proposes the concept of the "MDM2/Notch-ferroptosis axis," revealing its three-dimensional network that drives immune evasion and organ-specific metastasis through metabolic reprogramming hubs (mitochondrial dysfunction, lipid peroxidation, and redox imbalance). The specific mechanisms include: Molecular interactions: MDM2 ubiquitination and degradation of NUMB activates Notch, stabilizes GPX4 to inhibit ferroptosis; Notch1 directly binds to GPX4 to maintain its activity, while the MDM2-p53 axis downregulates SLC7A11 to promote ferroptosis, forming a dynamic balance. Metabolism-immune evasion: The axis weakens T-cell function and promotes tumor immune tolerance by reducing mitochondrial respiration, altering lipid metabolism (e.g., lipid droplet accumulation), and regulating immune checkpoints (PD-L1). Organ metastasis mechanisms: Metabolic reprogramming (e.g., EMT and iron homeostasis imbalance) endows metastatic cells with ferroptosis resistance, driving directional metastasis to lymph nodes, lungs, and liver, with stromal cell metabolism and an immunosuppressive microenvironment being key. Therapeutic contradictions and strategies: Targeted therapies face contradictions of activation and resistance rebound, while spatiotemporally specific interventions (e.g., photocontrolled nanodelivery and smart hydrogels) can precisely induce ferroptosis and synergize with immunotherapy. This review provides new strategies for targeting the axis network, advancing precision cancer therapy.
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