miR-145-5p induces ferroptosis by targeting Notch2 to suppress melanoma progression

Melanoma exhibits high malignancy with limited treatment options, while the newly defined type of programmed cell death, ferroptosis, presents a promising therapeutic avenue for melanoma. Notch2 has been implicated as a pivotal regulator of ferroptosis, yet its impact on melanoma and the upstream regulation remain elusive.

The TCGA data were used to correlate Notch2 expression with patient prognosis. Potential binding sites of miR-145-5p and Notch2 were predicted with starbase database. The levels of Notch2 and miR-145-5p in human melanoma tissues and cell lines were quantified via RT-qPCR, and their expression correlation was calculated. A875 cells were treated with si-Notch2 or ferrostatin-1. GSH content, GPX4 activity, ferrous ion level, cell viability, mortality and apoptosis were measured to evaluate the influence of Notch2 expression on ferroptosis and cell viability. Dual-luciferase reporter assays were involved to verify direct binding of miR-145-5p and Notch2 3'UTR. The miR-145-5p mimic or oe-Notch2 was transfected into A875 cells to validate the mechanism of miR-145-5p promoting ferroptosis in melanoma via Notch2.

Notch2 was markedly upregulated in melanoma and associated with poor survival. Knockdown of Notch2 activated ferroptosis and attenuated cell viability. miR-145-5p bound the Notch2 3'UTR and repressed its expression. Overexpression of miR-145-5p reversed Notch2-mediated ferroptosis resistance, elevated cell death, and augmented apoptosis.

miR-145-5p targets Notch2 to activate ferroptosis and curb melanoma progression. The study offers a novel therapeutic rationale for ferroptosis-based melanoma treatment.