BACKGROUND: Brain tumors, both primary and metastatic, are the main cause of cancer-associated mortality leading to patients' poor quality-of-life that remain as a global challenge. This study aims to identify the hub molecular controlling brain cancer progression, and establish corresponding prognostic index and therapeutic modality for improved brain cancer management. METHOD: We performed pan-cancer analysis unifying 9 publicly available datasets of cancers metastasized to the brain from different organs to identify the hub gene feasible for brain cancer prognosis. We conducted a series of computational analysis of the identified hub gene in primary gliomas to assess its diagnostic value. We investigated the potency and safety of cold atmospheric plasma (CAP) in treating brain cancers via targeting this hub molecule both in vitro and in vivo using glioma cells as the disease model. RESULTS: We identified CD44 as the nexus of brain cancer prognosis and therapeutics that should be applicable to both primary and metastatic brain cancers. We, in addition, constructed a CD44-dependent unified index for brain cancer overall survival prognosis
and proposed CAP as a highly promising approach for arresting brain cancers via targeting CD44. CONCLUSIONS: We are the first to characterize the relevance of CD44 with brain cancers by integrating its values on prognosis and therapeutics, as well as unifying its application scenarios in primary and metastatic brain cancers. Our work may spark innovative theranostic design for improved brain cancer management besides solutions provided by this study.