Dauricine induces ferroptosis in neuroblastoma by inhibiting methyltransferase-like 1-mediated N7-methylguanosine methylation of solute carrier family 3 member 2.

Abstract

Neuroblastoma is one of the most common extracranial solid tumors in children, characterized by high heterogeneity, aggressive biological behavior, and poor clinical prognosis. Ferroptosis, a form of programmed cell death driven by iron accumulation and lipid peroxidation, has been reported to be closely associated with neuroblastoma progression. Dauricine (Dau), a bisbenzylisoquinoline alkaloid extracted from traditional Chinese medicine, has demonstrated antitumor activity, but its role in regulating ferroptosis in neuroblastoma remains unclear. Cell viability, apoptosis, invasion, stemness, and angiogenesis were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxynucleotidyl transferase dUTP nick end labeling, transwell, sphere formation, and tube formation assays, respectively. Ferroptosis-related indicators were detected using corresponding commercial kits. The methyltransferase-like 1 (METTL1)-mediated N7-methylguanosine (m7G) methylation of solute carrier family 3 member 2 (SLC3A2) was examined through methylated RNA immunoprecipitation. RNA immunoprecipitation and RNA pull-down assays were conducted to confirm the interaction between METTL1 and SLC3A2 mRNA. Real-time quantitative PCR and western blotting were utilized to assess mRNA and protein expression, respectively. Molecular docking was performed to evaluate the potential binding interaction between Dau and METTL1. A xenograft tumor model was used for in vivo validation. The results showed that Dau inhibited neuroblastoma cell progression and promoted ferroptosis, while overexpression of SLC3A2 countered these effects. METTL1 mediated the m7G methylation of SLC3A2. Overexpression of SLC3A2 reversed the inhibition of neuroblastoma cell progression and the promotion of ferroptosis caused by METTL1 knockdown. Dau suppressed METTL1 expression, thus inhibiting neuroblastoma cell progression and promoting ferroptosis. Additionally, Dau reduced tumor growth in vivo. Together, Dau enhanced ferroptosis and impeded neuroblastoma development by suppressing METTL1-mediated m7G methylation of SLC3A2, suggesting a novel therapeutic strategy for neuroblastoma.