GINS1 suppresses ferroptosis by inhibiting the Hippo pathway in neuroblastoma

Background Neuroblastoma (NBL) prognosis remains poor in high-risk cases. Ferroptosis is a promising therapeutic target, but its regulation in NBL is unclear. This study investigates GINS1's role in NBL ferroptosis.Methods Bioinformatics analysis (GSE49710, GSE73517, TARGET) assessed GINS1 expression and prognosis. In vitro, GINS1 was knocked down in SH-SY5Y and SK-N-SH cells. Proliferation (CCK-8), migration (Transwell), apoptosis, and ferroptosis markers (lipid peroxidation, Fe2+, ACSL4, p-YAP) were evaluated. Rescue experiments involved ACSL4 overexpression.Results GINS1 knockdown in SH-SY5Y and SK-N-SH cells inhibited proliferation (60% reduction in SH-SY5Y cells and 55% in SK-N-SH cells, p < 0.001), migration (2.1-fold decrease in SH-SY5Y cells and 1.8-fold decrease in SK-N-SH cells, p < 0.001), and induced ferroptosis, evidenced by elevated lipid peroxidation (2.5-fold MDA increase, 1.8-fold Fe2+ increase, p < 0.001), upregulation of ACSL4, and increased p-YAP. Mechanistically, GINS1 ablation activates the Hippo pathway (evidenced by increased p-YAP and elevated p-YAP/YAP ratio), leading to YAP inactivation and subsequent derepression of ACSL4, thereby promoting ferroptosis. Rescue experiments confirmed that ACSL4 overexpression in GINS1-overexpressing cells antagonized tumor-promoting effects.Conclusion GINS1 suppresses ferroptosis via Hippo pathway inhibition and YAP activation, leading to ACSL4 repression. GINS1 is a potential prognostic biomarker and therapeutic target in high-risk NBL.