Pediatric brain tumors represent a formidable challenge in the field of oncology. Pediatric brain tumors are sub-classified into several molecular sub-types, where each one is characterized by an array of hyperactivated oncogenic molecular engines. However, there have been great efforts dedicated to portray the involved signaling pathways driving pediatric brain tumors. Yet, a full understanding of the intertwined oncogenic pathways involved is still obscure. In this review, the authors shed light on novel therapeutic targets tailored for several sub-types of pediatric brain tumors and point out the limitations of such therapeutic approaches. Hydrogen Sulfide (H2S) has recently been cast as an oncogenic driver in several solid malignancies, yet its role in brain tumors is still under investigation. The authors also highlight the possible involvement of H2S in pediatric brain tumors and propose promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumors patients.Abstract: Pediatric primary brain tumors represent a real challenge in the oncology arena. Besides the psychosocial burden, brain tumors are considered one of the most difficult-to-treat malignancies due to their sophisticated cellular and molecular pathophysiology. Notwithstanding the advances in research and the substantial efforts to develop a suitable therapy, a full understanding of the molecular pathways involved in primary brain tumors is still demanded. On the other hand, the physiological nature of the blood–brain barrier (BBB) limits the efficiency of many available treatments, including molecular therapeutic approaches. Hydrogen Sulfide (H2S), as a member of the gasotransmitters family, and its synthesizing machinery have represented promising molecular targets for plentiful cancer types. However, its role in primary brain tumors, generally, and pediatric types, particularly, is barely investigated. In this review, the authors shed the light on the novel role of hydrogen sulfide (H2S) as a prominent player in pediatric brain tumor pathophysiology and its potential as a therapeutic avenue for brain tumors. In addition, the review also focuses on the challenges and opportunities of several molecular targeting approaches and proposes promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumor patients.

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