Objective The objective of this study is to determine how gliogenic regulators impact the Pilocytic Astrocytoma tumorigenesis and what it has to do with the benign nature of Pilocytic Astrocytoma.

Background Pilocytic Astrocytoma (PA) is a benign pediatric brain tumor driven by gliogenic signaling dysregulation, particularly the MAPK/ERK pathway. Unlike high-grade gliomas, PA maintains differentiation cues that limit malignancy. Investigating gliogenic transcription factors, tumor suppressors, and signaling pathways can reveal how PA sustains proliferation without aggressive transformation. This research bridges oncogenic drivers and gliogenic regulation, offering insights into potential therapies and strategies to prevent malignant progression in gliomas.

Methods Databases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for articles without any date restrictions, to investigate how gliogenic regulators impact the key PA tumorigenesis regulators and what it has to do with the benign nature of Pilocytic Astrocytoma. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate the research question. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Results This study reveals that Pilocytic Astrocytoma (PA) originates through gliogenic differentiation-linked oncogenesis, primarily driven by MAPK/ERK pathway hyperactivation via BRAF fusion or NF1 loss. Despite oncogenic signaling, PA remains benign due to intact PTEN, TP53, and differentiation-linked transcription factors (SOX10, NFIs, PAX6), which suppress uncontrolled proliferation. The tumor microenvironment further restricts angiogenesis and invasion, reinforcing its low malignancy risk. Key glial regulatory pathways, including Notch, Shh, and JAK/STAT, contribute to sustained astrocytic differentiation rather than dedifferentiation. Additionally, PI3K/AKT/mTOR signaling remains tightly controlled, preventing high-grade transformation.

These findings refine our understanding of benign glioma oncogenesis, distinguishing PA from aggressive gliomas like glioblastoma. Identifying molecular players in PA’s stability offers potential biomarkers for diagnosis and suggests differentiation-inducing therapies as a promising approach to limiting tumor progression.

Conclusion Pilocytic Astrocytoma (PA) remains benign due to controlled MAPK/ERK activation, gliogenic transcription factors (PAX6, NFIA, STAT3, SOX10) promoting differentiation, and limited activation of oncogenic pathways (PI3K/AKT, JAK/STAT, Notch, Shh). Low invasiveness, restricted angiogenesis, and a non-immunosuppressive microenvironment prevent malignant transformation. PA lacks genetic instability, avoiding mutations that drive high-grade gliomas. Its gliogenic framework ensures regulated growth, differentiation, and genomic stability, preventing dedifferentiation or invasiveness, solidifying PA as a benign, non-malignant glioma with stable cellular behavior and limited tumor progression potential.

The authors have declared no competing interest.

I declare that there was not any source of funding for this research work.

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