Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.

Background: Despite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6‐methyladenosine (m⁶A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m⁶A modification in the regulation of TMZ resistance in GBM remain unclear.Methods: m⁶A individual‐nucleotide‐resolution cross‐linking and immunoprecipitation sequencing (miCLIP‐seq) was performed to identify m⁶A modification of transcripts in TMZ‐resistant and ‐sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ‐resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC‐seq, ChIP‐qPCR, and dual‐luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment.Results: We demonstrated that TMZ treatment upregulated the expression of the m⁶A methyltransferase METTL3, thereby increasing m⁶A modification of histone modification‐related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ‐resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4‐mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m⁶A on histone modification‐related gene transcripts, such as EZH2, leading to nonsense‐mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification‐independent manner.Conclusions: Our findings uncover the fundamental mechanisms underlying the interplay of m⁶A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ‐resistant GBM.

High‐grade meningioma has an unsatisfactory outcome despite surgery and postoperative radiotherapy; however, the factors driving its malignancy and recurrence remain largely unknown, which limits the development of systemic treatments. Single‐cell RNA sequencing (scRNA‐Seq) technology is a powerful tool for studying intratumoral cellular heterogeneity and revealing the roles of various cell types in oncogenesis. In this study, scRNA‐Seq is used to identify a unique initiating cell subpopulation (SULT1E1⁺) in high‐grade meningiomas. This subpopulation modulates the polarization of M2‐type macrophages and promotes meningioma progression and recurrence. A novel patient‐derived meningioma organoid (MO) model is established to characterize this unique subpopulation. The resulting MOs fully retain the aggressiveness of SULT1E1⁺ and exhibit invasiveness in the brain after orthotopic transplantation. By targeting SULT1E1⁺ in MOs, the synthetic compound SRT1720 is identified as a potential agent for systemic treatment and radiation sensitization. These findings shed light on the mechanism underlying the malignancy of high‐grade meningiomas and provide a novel therapeutic target for refractory high‐grade meningioma.

Glioblastoma (GBM) is the most common and lethal malignant primary brain tumor. The standard treatment for GBM including surgical resection followed by radiation therapy and adjuvant chemotherapy with temozolomide remains unsatisfactory. In this study, we investigated the effects of the Aurora kinase inhibitor, TAK901, in GBM both in vitro and in vivo, and explored its key downstream targets. The effects of TAK901 were investigated using cell viability, cell apoptosis, live/dead, cell cycle, Transwell, 3D cell invasion, neuro-sphere, and self-renewal assays. Mechanistic studies were conducted using RNA-seq, lipid measurements, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western blotting. The in vivo efficacy of TAK901 was validated using orthotopic xenograft GBM mouse models. In both GBM cells and GSCs, TAK901 remarkably reduced cell viability, self-renewal, migration and invasion and induced apoptosis and cell cycle arrest. Treatment with TAK901 considerably inhibited GBM growth in vivo. RNA-seq and RT-qPCR analyses showed that TAK901 downregulated the expression and activation of SREBP1. Moreover, SREBP1 overexpression alleviated the TAK901-mediated suppression of cell viability and apoptosis in GBM cells. Our results provide evidence that TAK901 inhibits GBM growth by suppressing SREBP1-mediated lipid metabolism.