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Leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) functions as a tumor suppressor in glioma. Although our previous study demonstrated that LRIG3 inhibited angiogenesis via the PI3K/AKT/VEGFA pathway under normoxia, its impact on glioma vascularization under hypoxia remains elusive. Vasculogenic mimicry (VM), an alternative form of neovascularization, plays a pivotal role in glioma progression, particularly within hypoxic tumor microenvironments. This study aimed to investigate the effects of LRIG3 on hypoxia-induced VM in glioma and to elucidate the underlying molecular mechanisms. The effects of LRIG3 on VM were evaluated in vitro using tube formation and 3D spheroid invasion assays. Histological analysis of intracranial xenografts and glioblastoma specimens was performed to assess LRIG3's impact on glioma vascularization in vivo. The underlying mechanisms were investigated using western blot, quantitative real-time PCR (qRT-PCR), and ubiquitination assays. LRIG3 expression was inversely correlated with VM density in the central hypoxic regions of both xenografts and glioblastoma specimens. Under hypoxia, LRIG3 overexpression inhibited the invasion and tube formation capacities of glioma cells, whereas its knockdown promoted these activities. Mechanistically, LRIG3 suppressed VM phenotypes by downregulating Snail2 at the post-translational level, rather than affecting VEGFA. LRIG3 promoted the ubiquitination of Snail2, leading to its proteasomal degradation and destabilization under hypoxia. LRIG3 inhibits hypoxia-induced VM in glioma by facilitating the proteasomal degradation of Snail2 via ubiquitination.

The mesenchymal (MES) subtype of glioblastoma (GBM) is a highly aggressive, malignant and proliferative cancer that is resistant to chemotherapy. Runt-related transcription factor 1 (RUNX1) was shown to support MES GBM, however, its underlying mechanisms are unclear. Here, we identified USP10 as a deubiquitinating enzyme that regulates RUNX1 stabilization and is mainly expressed in MES GBM. Overexpression of USP10 upregulated RUNX1 and induced proneural-to-mesenchymal transition (PMT), thus maintaining MES properties in GBM. Conversely, USP10 knockdown inhibited RUNX1 and resulted in the loss of MES properties. USP10 was shown to interact with RUNX1, with RUNX1 being stabilized upon deubiquitylation. Moreover, we found that USP10 inhibitor Spautin-1 induced RUNX1 degradation and inhibited MES properties in vitro and in vivo. Furthermore, USP10 was strongly correlated with RUNX1 expression in samples of different subtypes of human GBM and had prognostic value for GBM patients. We identified USP10 as a key deubiquitinase for RUNX1 protein stabilization. USP10 maintains MES properties of GBM, and promotes PMT of GBM cells. Our study indicates that the USP10/RUNX1 axis may be a potential target for novel GBM treatments.

The activation of epithelial–mesenchymal transition (EMT) promotes glioblastoma (GBM) invasion, thereby enhancing its malignancy. Elucidating the underlying mechanisms that regulate EMT is essential for the development of effective treatments for GBM. In this study, we found that GBM tissues and cells exhibit significantly elevated expression levels of ataxin 3 (ATXN3). Functional experiments demonstrated that ATXN3 promotes the invasion, migration, and tumor growth of GBM cells by activating EMT. Mechanistically, ATXN3 was identified as a bona fide deubiquitinase for ZEB1, a key EMT-inducing transcription factor, in GBM cells. ATXN3 interacts directly with ZEB1, cleaves ubiquitin moieties from conjugated substrates and maintains the stability of ZEB1. Ectopic expression of ZEB1 significantly mitigates the inhibitory effects of ATXN3 depletion on the invasion, migration, and tumor growth of GBM cells. Furthermore, ATXN3 exhibits a positive correlation with ZEB1 expression levels and serves as a predictor of poor prognosis in human GBM specimens. Collectively, our study elucidates a critical ATXN3–ZEB1 signaling axis in EMT and invasion, thereby providing a rationale for potential therapeutic interventions against GBM.

Background Neuromyelitis optica spectrum disorder (NMOSD) is an autoantibody-triggered central nervous system (CNS) demyelinating disease that primarily affects the spinal cord, optic nerves and brainstem. Among the first responders to CNS injury, microglia are prominent players that drive NMOSD lesion formation. However, the key molecular switches controlling the detrimental activity of microglia in NMOSD are poorly understood. CD22 governs the activity of innate and adaptive immunity. In this study, we investigated to what extent and by what mechanisms CD22 may modulate microglial activity, neuroinflammation and CNS lesion formation. Methods To determine the expression profile of CD22 in NMOSD, we performed single-cell sequencing and flow cytometry analysis of immune cells from human peripheral blood. We investigated the potential effects and mechanisms of CD22 blockade on microglial activity, leukocyte infiltration and CNS demyelination in a mouse model of NMOSD induced by injection of NMOSD patient serum-derived AQP4-IgG and human complement. Results Single-cell sequencing and flow cytometry analysis revealed that CD22 was expressed in B cells, neutrophils, monocytes and microglia-derived exosomes in human peripheral blood from NMOSD patients and controls ( n  = 5 per group). In a mouse model of NMOSD, CD22 was expressed in B cells, neutrophils, monocytes and microglia ( n  = 8 per group). In NMOSD mice, CD22 blockade significantly increased the number of CNS lesions, astrocyte loss and demyelination, accompanied by increased inflammatory activity and phagocytosis in microglia. Furthermore, the detrimental effects of CD22 blockade were significantly alleviated in NMOSD mice subjected to depletion of microglia or Gr-1 + myeloid cells, suggesting the involvement of microglia and peripheral Gr-1 + myeloid cells. Additionally, CD22 blockade also led to significantly reduced phosphorylation of SYK and GSK3β in NMOSD. Notably, the detrimental effects of CD22 blockade were greatly diminished in NMOSD mice receiving the phosphorylated SYK inhibitor R406. Conclusions Our findings revealed a previously unrecognized role of CD22 as a key molecular switch that governs the detrimental effects of microglia and Gr-1 + myeloid cells in NMOSD, which paves the way for the future design of immune therapies for NMOSD. Graphical abstract

Background Alternative polyadenylation (APA) is a critical post-transcriptional regulatory mechanism involved in various diseases. Studies have shown dysfunction of APA-regulating factors such as SRSF10 in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the downstream target genes and functional consequences remain unclear. This study investigated the role of APA in modulating LPGAT1 expression in MASLD. Methods Integrative analyses of bulk and single-cell RNA sequencing data from human and mouse MASLD livers were performed to identify APA changes. Functional validations were conducted using lysophosphatidylglycerol acyltransferase 1 ( LPGAT1 ) 3’ UTR (3’ untranslated region)-knockout HepG2 cells under free fatty acid (FFA) treatment. Results Early hepatocyte-specific APA remodeling characterized by 3’ lengthening of metabolism-related genes, especially LPGAT1 , was observed in MASLD. Despite elevated LPGAT1 mRNA levels, protein levels were suppressed in MASLD, associated with an increased usage of a proximal 3’ UTR segment enriched with miRNA binding sites. Deletion of this proximal region in HepG2 cells restored LPGAT1 protein levels and mitigated lipid accumulation under FFA exposure. Conclusions This study establishes a cell type-resolved APA regulatory map for the MASLD liver and identifies APA-mediated repression of LPGAT1 as a critical driver of hepatic lipid accumulation. These findings highlight APA regulation as not only a pathogenic mechanism but also a promising molecular target for therapeutic interventions aimed at combating the progression of metabolic liver disease.

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a dismal prognosis, particularly in its mesenchymal (MES) subtype, which correlates strongly with poor survival. Despite this, the mechanisms preserving MES identity remain poorly understood. Here, we show that alpha-actinin 1 (ACTN1) is upregulated in MES GBM and drives proneural-to-mesenchymal transition (PMT). Using patient samples and multiple GBM cell lines, we find that ACTN1 overexpression promotes proliferation, invasion, and tumorigenesis, while its silencing diminishes these malignant traits and shifts gene expression away from MES markers. Mechanistically, we identify ubiquitin-specific peptidase 14 (USP14) as a pivotal deubiquitinase (DUB) that stabilizes ACTN1 by removing its ubiquitin chains. Pharmacological inhibition of USP14 with IU1 reduces ACTN1 protein levels, impairs MES-associated phenotypes, and suppresses tumor progression in vitro and in intracranial xenograft models. Clinically, elevated USP14 and ACTN1 expression correlates with poorer survival in GBM patients, highlighting the USP14–ACTN1 axis as a key driver of PMT and a promising therapeutic target for this devastating disease. USP14 deubiquitinates and stabilizes ACTN1 to sustain the mesenchymal state of glioblastoma and drive tumor growth; clinically, elevated USP14/ACTN1 predicts poorer survival.

Objectives: Glioma is the most common and aggressive type of primary central nervous system (CNS) tumor in adults and is associated with substantial mortality rates. The aim of our study was to evaluate the prognostic significance and function of the complement factor I (CFI) in glioma. Materials and Methods: The expression levels of CFI in glioma tissues and the survival of the CFI high and CFI low patient groups were analyzed using The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx). The correlation between CFI expression and clinicopathological features of glioma was determined by univariate and multivariate Cox regression analyses in the Chinese Glioma Genome Atlas (CGGA) database. The functional role of CFI in glioma was established through routine in vitro and in vivo assays. Results: CFI is overexpressed in glioma and its high levels correlated with poor outcomes in both TCGA and CGGA datasets. Furthermore, CFI was identified as an independent prognostic factor of glioma in the CGGA database. CFI knockdown in glioma cell lines inhibited growth in vitro and in vivo , whereas its ectopic expression increased glioma cell proliferation, migration, and invasion in vitro . CFI protein levels were also significantly higher in the glioma tissues resected from patients and correlated to worse prognosis. Conclusions: CFI is a potential prognostic biomarker in glioma and drives malignant progression.

Leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) functions as a tumor suppressor in glioma. Although our previous study demonstrated that LRIG3 inhibited angiogenesis via the PI3K/AKT/VEGFA pathway under normoxia, its impact on glioma vascularization under hypoxia remains elusive. Vasculogenic mimicry (VM), an alternative form of neovascularization, plays a pivotal role in glioma progression, particularly within hypoxic tumor microenvironments. This study aimed to investigate the effects of LRIG3 on hypoxia-induced VM in glioma and to elucidate the underlying molecular mechanisms.PURPOSELeucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) functions as a tumor suppressor in glioma. Although our previous study demonstrated that LRIG3 inhibited angiogenesis via the PI3K/AKT/VEGFA pathway under normoxia, its impact on glioma vascularization under hypoxia remains elusive. Vasculogenic mimicry (VM), an alternative form of neovascularization, plays a pivotal role in glioma progression, particularly within hypoxic tumor microenvironments. This study aimed to investigate the effects of LRIG3 on hypoxia-induced VM in glioma and to elucidate the underlying molecular mechanisms.The effects of LRIG3 on VM were evaluated in vitro using tube formation and 3D spheroid invasion assays. Histological analysis of intracranial xenografts and glioblastoma specimens was performed to assess LRIG3's impact on glioma vascularization in vivo. The underlying mechanisms were investigated using western blot, quantitative real-time PCR (qRT-PCR), and ubiquitination assays.METHODSThe effects of LRIG3 on VM were evaluated in vitro using tube formation and 3D spheroid invasion assays. Histological analysis of intracranial xenografts and glioblastoma specimens was performed to assess LRIG3's impact on glioma vascularization in vivo. The underlying mechanisms were investigated using western blot, quantitative real-time PCR (qRT-PCR), and ubiquitination assays.LRIG3 expression was inversely correlated with VM density in the central hypoxic regions of both xenografts and glioblastoma specimens. Under hypoxia, LRIG3 overexpression inhibited the invasion and tube formation capacities of glioma cells, whereas its knockdown promoted these activities. Mechanistically, LRIG3 suppressed VM phenotypes by downregulating Snail2 at the post-translational level, rather than affecting VEGFA. LRIG3 promoted the ubiquitination of Snail2, leading to its proteasomal degradation and destabilization under hypoxia.RESULTSLRIG3 expression was inversely correlated with VM density in the central hypoxic regions of both xenografts and glioblastoma specimens. Under hypoxia, LRIG3 overexpression inhibited the invasion and tube formation capacities of glioma cells, whereas its knockdown promoted these activities. Mechanistically, LRIG3 suppressed VM phenotypes by downregulating Snail2 at the post-translational level, rather than affecting VEGFA. LRIG3 promoted the ubiquitination of Snail2, leading to its proteasomal degradation and destabilization under hypoxia.LRIG3 inhibits hypoxia-induced VM in glioma by facilitating the proteasomal degradation of Snail2 via ubiquitination.CONCLUSIONSLRIG3 inhibits hypoxia-induced VM in glioma by facilitating the proteasomal degradation of Snail2 via ubiquitination.

Glioma is the most common primary tumour in central nervous system, characterized by high invasiveness, a high recurrence rate and extremely poor prognosis. Machine learning based on cancer functional state helps to combine multi‐omics methods to screen for key gene, such as CENPA, that influences the phenotype of glioma and patients' prognosis. Based on 14 CFS, glioma was divided into three subtypes. Bioinformatics and machine learning methods were utilized to develop an enhanced prognostic prediction signature based on three subtypes. We selected CENPA as a hub biomarker and conducted in vitro experiments such as IHC, western blot, Coip, transwell, cck8, flow cytometry, scratch assay, qPCR, AlphaFold, MOE and in vivo experiments. We identified three subtypes of glioma based on the 14 CFS. The C subtype exhibits poor clinical outcomes, increased carbohydrate and nucleotide metabolism, high infiltration of immune cells, high CNV and tumour mutation burden (p < 0.05). The differential expression of gene between three subtypes were used to construct a novel signature with improved performance in prognostic prediction via machine learning. CENPA was selected as the hub gene, in vitro experiments such as ihc, western blot and qPCR showed that CENPA had high expression in tissues and cell lines (p < 0.05). The scratch assay, edu, cck8, flow cytometry and transwell after CENPA knockdown or overexpression had significant effects on the functions of glioma. Meanwhile, CENPA was regulated by EZH2 and influenced downstream wnt pathway, affecting phosphorylation of two sites, Ser675 and Ser552, on β‐catenin. The effect of CENPA knockdown was reversed by drug CHIR‐99021. Animal experiments indicated that the tumour volume of control and overexpression group increased faster, especially the overexpression group, which was significantly faster (p < 0.001). Machine learning based on CFS is beneficial for the selection of key genes and disease assessment. In glioma, CENPA is positively correlated with WHO grading at both the gene and protein levels, and high CENPA affects patients' poor prognosis. Regulating CENPA can affect functions of glioma, and these phenomena may act through the EZH2/CENPA/β‐catenin signalling axis. CENPA knockdown can be reversed by the drug CHIR‐99021. CENPA may become one of the therapeutic targets in glioma.

PurposeMicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of glioma. However, the underlying molecular mechanisms are still unclear.MethodsWe performed microarray analysis to evaluate miRNA expression levels in 158 glioma tissue samples, and examined miR-1231 levels in glioma samples and healthy brain tissues using qRT-PCR. In vitro analyses were performed using miR-1231 mimics, inhibitors, and siRNA targeting EGFR. We used flow cytometry, CCK-8 assays, and colony formation assays to examine glioma proliferation and cell cycle analysis. A dual luciferase reporter assay was performed to examine miR-1231 regulation of EGFR, and the effect of upregulated miR-1231 was investigated in a subcutaneous GBM model.ResultsWe found that miR-1231 expression was decreased in human glioma tissues and negatively correlated with EGFR levels. Moreover, the downregulation of miR-1231 negatively correlated with the clinical stage of human glioma patients. miR-1231 overexpression dramatically downregulated glioma cell proliferation, and suppressed tumor growth in a nude mouse model. Bioinformatics prediction and a luciferase assay confirmed EGFR as a direct target of miR-1231. EGFR overexpression abrogated the suppressive effect of miR-1231 on the PI3K/AKT pathway and G1 arrest.ConclusionsTaken together, these results demonstrated that EGFR is a direct target of miR-1231. Our findings suggest that the miR-1231/EGFR axis may be a helpful future diagnostic target for malignant glioma.