Deubiquitinating Enzymes as Emerging Therapeutic Targets in Pediatric Malignancies

Pediatric malignancies remain the leading cause of disease-related mortality in children under 14 years of age. Although risk-stratified chemotherapy and multidisciplinary combination therapies have significantly improved overall survival rates, high-risk subtypes—such as relapsed/refractory neuroblastoma, diffuse intrinsic pontine glioma, and high-risk leukemias—still carry dismal prognoses. Furthermore, long-term survivors frequently suffer from severe, treatment-induced late complications, underscoring the urgent need for novel, low-toxicity targeted strategies.

The ubiquitin-proteasome system (UPS) serves as a central regulatory network for intracellular protein homeostasis. It involves over 500 human proteins that control ubiquitination and modulate key cellular signaling pathways. Countering this system, deubiquitinating enzymes (DUBs) remove ubiquitin chains from substrate proteins to reverse degradation signals, thereby regulating critical biological processes such as cell proliferation, differentiation, DNA damage repair, and apoptosis. Given their critical roles in oncogenic signaling, DUBs have emerged as highly promising therapeutic targets. However, several bottlenecks hinder their clinical translation: the physiological roles of DUBs in normal developing tissues remain poorly understood, the mechanisms driving tumor subtype-specific dependencies are largely uncharacterized, and toxicity data for DUB-targeted therapies in pediatric contexts remain insufficient.

Goal

This Research Topic aims to systematically consolidate recent advances in understanding the roles of deubiquitinating enzymes in the pathogenesis, therapeutic resistance, and targeted treatment of pediatric malignancies, ultimately accelerating the translation of DUB-directed strategies from bench to bedside. We seek to address several pivotal questions: Which DUBs exhibit “oncogenic addiction” in specific pediatric tumor subtypes? How can the anti-tumor efficacy of DUB inhibition be balanced against safety and tolerability in developing pediatric tissues? Which combination strategies (e.g., with chemotherapy or immunotherapy) can maximize the therapeutic window of DUB-targeted agents? Additionally, we encourage submissions utilizing multi-omics bioinformatics, functional CRISPR screens, and pharmacogenomic approaches to discover and validate novel, clinically actionable DUB targets. By bringing together cutting-edge findings, this collection aims to establish novel theoretical frameworks and candidate targets for precision pediatric oncology.

Scope and Information for Authors

This Research Topic welcomes original research, reviews, methodological advances, and opinion articles. Specific themes of interest include, but are not limited to:

• Expression profiles, mutational landscapes, and clinical prognostic correlations of key DUBs in pediatric malignancies (including neuroblastoma, brain tumors, leukemias, and bone/soft tissue sarcomas);
• Molecular mechanisms by which DUBs regulate oncogenic signaling pathways in pediatric cancers;
• Development and preclinical evaluation of novel DUB-targeting modalities (including small-molecule inhibitors, allosteric modulators, and PROTAC degraders);
• Synergistic combination strategies and resistance mechanisms of DUB-targeted agents when paired with chemotherapy, immunotherapy, or other targeted therapies;
• Multi-omics bioinformatics, functional CRISPR screens, and pharmacogenomic modeling for the systematic discovery and validation of novel DUB targets;
• Preclinical models and strategies to optimize the therapeutic window and minimize the toxicity of DUB-targeted therapies on developing pediatric tissues.