AUTHOR=Chen Yi , Yang Huixian , Xiao Lirong , Yan Naihong , Zhang Ming 

TITLE=Molecular regulation and therapeutic targeting of MYCN in neuroblastoma: a comprehensive review

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 13 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2025.1683331

DOI=10.3389/fcell.2025.1683331

ISSN=2296-634X

ABSTRACT=MYCN amplification defines a highly aggressive subtype of neuroblastoma and is strongly associated with poor clinical outcomes. Due to the intrinsically disordered structure of the N-Myc protein, it remains largely undruggable. This review provides a comprehensive summary of the molecular regulatory network surrounding MYCN, including upstream pathways, key cofactors, and downstream effectors involved in cell cycle control, metabolic reprogramming, and ferroptosis. We further discuss the roles of epigenetic modulators, noncoding RNAs, and positive feedback loops in sustaining MYCN-driven oncogenic programs. Emerging therapeutic strategies such as PROTACs, metabolic inhibitors, immune-based approaches, and RNA-targeting technologies offer promising alternatives to direct MYCN inhibition. This review aims to provide a theoretical foundation for future development of precise and effective therapies targeting MYCN-amplified neuroblastoma.