Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.

Glioblastoma (GBM) is the most malignant primary brain tumor, characterized by extensive heterogeneity, invasiveness, infiltrating behavior, and resistance to standard therapies, including radiation and temozolomide (TMZ). Despite considerable efforts in investigating its pathophysiology, GBM represents one of the most challenging cancers to treat, with a median survival rate under 15 months and a 5-year survival rate below 5%. A major barrier to progress in GBM therapy development is the lack of reliable preclinical models that faithfully recapitulate the tumor’s molecular heterogeneity, invasive behavior, and complex microenvironment. Traditional cell lines and xenograft models often fail to reflect the key pathological features of human GBM, including immune suppression, vascular abnormalities, and treatment resistance. In recent years, attention has focused on the development of numerous clinically relevant GBM models based on brain organoids as a powerful “disease-in-a-dish” model. They strongly mimic GBM key histopathological and molecular features, such as the tumor’s cellular heterogeneity, genetic landscape, and microenvironment, enabling more accurate studies of tumor biology, invasion, and therapeutic response in a controlled in vitro setting. Notably, research in microgravity offers a unique and promising platform to study cancer biology under conditions that enhance tissue self-organization, mimic aspects of tumor growth, and potentially unveil novel therapeutic vulnerabilities. This review compares organoids to conventional preclinical models, tracing their historical development and salient features, focusing on the preparation and use of organoids in GBM research. We also introduce a novel and promising field of organoid application: space-based organoid brain research.