## 4 Discussion  
In the present study, we utilized a bioinformatic approach to explore the potential of GPRC5A as a clinical biomarker in GBM. Our findings demonstrate a significant correlation between GPRC5A and various aggressive features of GBM tumorigenesis. Notably, GPRC5A is enriched in mesenchymal subtypes and correlated with several putative stemness markers in GBM, such as CD44, CD133, uPAR, and CXCR4. Additionally, its spatial distribution seems to be prominent in the pseudopalisade area of GBM, which is associated with high ECM and hypoxia features. Moreover, immune and stromal signatures indicate that GPRC5A is strongly linked to immunosuppression and the inflammation microenvironment. This is evidenced by the presence of immunosuppressive cells, like Tregs, MDSCs, and macrophages, alongside high levels of inflammatory immune cells, including NK dim cells, T helper cells, and neutrophils. Our analysis suggests that GPRC5A could serve as a valuable biomarker for identifying mesenchymal subtypes with stem cell phenotypes, particularly those enriched in the pseudopalisade areas of GBM. The mesenchymal subtype is considered the most aggressive form of GBM compared to the classical, neural, and proneural subtypes. It is often characterized by hypoxia, inflammation, and invasiveness, with a high infiltration of inflammatory immune cells [59]. Patients with the mesenchymal subtype typically have poorer outcomes due to the high invasiveness and multi-therapy resistance. This subtype is also associated with the deletion of tumor suppressor genes _TP53_, _PTEN_, and _NF1_, which further complicates treatment strategies [32]. In support of the literature, our predictions demonstrate a significant correlation between GPRC5A and several mesenchymal molecular features, such as hypoxia, EMT, and _NF1_ and _PTEN_ genetic mutations, indicating that GPRC5A can serve as a specific biomarker for stratifying patients with mesenchymal subtypes [60]. Given the role of GPRC5A in promoting several cellular processes, some studies have highlighted the role of GPRC5A as either a tumor suppressor or an oncogene, depending on the type of cancer [61]. In GBM, it has been shown that the deletion of GPRC5A abrogated cell proliferation in GBM cell lines [30]. This suggests that GPRC5A might act as an oncogene in GBM. However, further experimental investigations are needed to fully understand the potential role of GPRC5A, especially in mesenchymal subtypes. For example, the variation of GPRC5A expression can be assessed by Western blotting or quantitative PCR, in different sample types, such as GBM cell lines and patient-derived tumor samples, both untreated and treated with radiation or chemotherapy. Additionally, immunohistochemistry can be utilized to confirm the association between GPRC5A expression and various genetic alterations, providing further prognosis validation of its role in GBM. The stemness properties in GBM have been considered a problematic biological characteristic in GBM, as it represents one of the major causes of relapse and therapy resistance [19]. These stem-like cells are highly adapted to environmental cues and exhibit a spectrum of cell states with diverse biological programming. Their plasticity and heterogeneous phenotype make them difficult to isolate and characterize. Currently, GBM stem cells (GSCs) are identified based on several surface markers, including CD133, CD44, CD15, and CD70, with CD133 being the most prevalent. However, no specific marker or set of markers has been identified to exclusively characterize GSCs [7; 19; 62]. Given its cell surface expression and our prediction showing an association with CD44 and CD133, GPRC5A may serve as a potential marker for stem cell identification and cellular discrimination. GPRC5A has not been confirmed as a stem cell marker in GBM; however, [PERSON] et al.