Notch signaling and ferroptosis - Context-dependent regulation and therapeutic implications: A review.

Abstract

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, but its regulation by Notch signaling remains incompletely understood. This narrative review examines the mechanisms and disease relevance of Notch-ferroptosis interactions. Evidence from experimental models and patient-tissue analyses is synthesized into three categories: Notch-mediated regulation, indirect or Notch-independent associations, and Notch-induced ferroptosis sensitivity. In selected models, Notch activation suppresses ferroptosis by supporting nuclear factor E2-related factor 2 (NRF2)-dependent antioxidant defenses, maintaining selenium uptake, or stabilizing glutathione peroxidase 4 (GPX4). Conversely, loss of protective Notch signaling is associated with increased ferroptosis in hepatic stellate cells. Context-specific Notch-dependent promotion has been reported in hepatocellular carcinoma, although receptor-proximal mechanisms remain unresolved. In glioblastoma, Notch activation creates a metabolically vulnerable state that increases ferroptosis susceptibility without directly initiating ferroptosis. Other reported relationships involve Notch-independent mechanisms or remain associative. Cell type, metabolic state, and microenvironment contribute to these divergent outcomes. Overall, the evidence is predominantly preclinical, with direct causal support restricted to selected models and limited clinical validation. Therapeutic strategies targeting Notch-ferroptosis interactions should therefore be tailored to the underlying mechanism and disease context, with further mechanistic confirmation and clinical validation required before therapeutic translation.