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Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway’s steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability.

To compare the efficacies of univariate and radiomics analyses of amide proton transfer weighted (APT ) imaging in predicting isocitrate dehydrogenase 1 ( ) mutation of grade II/III gliomas. Fifty-nine grade II/III glioma patients with known mutation status were prospectively included ( wild type, 16; mutation, 43). A total of 1044 quantitative radiomics features were extracted from APT images. The efficacies of univariate and radiomics analyses in predicting mutation were compared. Feature values were compared between two groups with independent test and receiver operating characteristic (ROC) analysis was applied to evaluate the predicting efficacy of each feature. Cases were randomly assigned to either the training ( = 49) or test cohort ( = 10) for the radiomics analysis. Support vector machine with recursive feature elimination (SVM-RFE) was adopted to select the optimal feature subset. The adverse impact of the imbalance dataset in the training cohort was solved by synthetic minority oversampling technique (SMOTE). Subsequently, the performance of SVM model was assessed on both training and test cohort. As for univariate analysis, 18 features were significantly different between wild-type and mutant groups ( < 0.05). Among these parameters, achieved the biggest area under the curve (AUC) (0.769) with the accuracy of 0.799. As for radiomics analysis, SVM model was established using 19 features selected with SVM-RFE. The AUC and accuracy for mutation on training set were 0.892 and 0.952, while on the testing set were 0.7 and 0.84, respectively. Radiomics strategy based on APT image features is potentially useful for preoperative estimating mutation status.

IntroductionMutations in isocitrate dehydrogenase 1/2 (IDHmut) identify a subset of gliomas that exhibit epigenetic dysregulation via aberrant DNA methylation. These tumors are ultimately fatal and lack effective therapeutic strategies. Considering the epigenetic dysregulation of IDHmut gliomas, we hypothesized that epigenetic-targeting drugs may yield therapeutic benefits in gliomas bearing IDHmut. One set of targets includes the bromodomain and extraterminal (BET) family of transcriptional coactivators.MethodsWe used TCGA data from glioma patients to determine whether BET proteins affect patient survival differently based on IDH status. Follow-up experiments using a set of IDH wildtype/mutant glioma cultures, as well as an IDH wildtype glioblastoma cell line expressing exogenous R132H IDH1, focused on cell health assays to investigate whether IDHmut was associated with increased sensitivity to the BET inhibitor JQ1. Immunoblots were used to evaluate the molecular response to JQ1 in these cultures.ResultsWe identified that high BRD4 expression associated with decreased survival only in IDHmut glioma patients. Cell viability analysis showed that IDHmut sensitized glioma cells to delayed cytotoxicity (10 days) in response to JQ1. Early effects of JQ1 (3 days) were primarily antiproliferative, with IDHmut glioma exhibiting a modest increase in sensitivity. Finally, exogenous R132H IDH1 expression in a resistant IDH wildtype cell line recapitulated the JQ1-mediated delayed cytotoxicity seen in our endogenous IDHmut glioma cells.ConclusionOverall, these data suggest that BRD4 enhances malignancy primarily in gliomas bearing IDHmut and is associated with greater sensitivity to BET inhibition. The finding that BET inhibition primarily exhibits delayed cytotoxicity may be overlooked in conventional short endpoint dose–response assays. Follow-up mechanistic and animal studies will help address the translational potential of these findings.

Isocitrate dehydrogenase1 (IDH1) mutation is the most important genetic change in glioma. The most common IDH1 mutation results in the amino acid substitution of arginine 132 (Arg/R132), which is located at the active site of the enzyme. IDH1 Arg132His (R132H) mutation can reduce the proliferative rate of glioma cells. Numerous diseases follow circadian rhythms, and there is growing evidence that circadian disruption may be a risk factor for cancer in humans. Dysregulation of the circadian clock serves an important role in the development of malignant tumors, including glioma. Brain-Muscle Arnt-Like protein 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are the main biological rhythm genes. The present study aimed to further study whether there is an association between IDH1 R132H mutation and biological rhythm in glioma, and whether this affects the occurrence of glioma. The Cancer Genome Atlas (TCGA) database was used to detect the expression levels of the biological rhythm genes BMAL1 and CLOCK in various types of tumor. Additionally, U87-MG cells were infected with wild-type and mutant IDH1 lentiviruses. Colony formation experiments were used to detect cell proliferation in each group, cell cycle distribution was detected by flow cytometry and western blotting was used to detect the expression levels of wild-type and mutant IDH1, cyclins, biological rhythm genes and Smad signaling pathway-associated genes in U87-MG cells. TCGA database results suggested that BMAL1 and CLOCK were abnormally expressed in glioma. Cells were successfully infected with wild-type and mutant IDH1 lentiviruses. Colony formation assay revealed decreased cell proliferation in the IDH1 R132H mutant group. The cell cycle distribution detected by flow cytometry indicated that IDH1 gene mutation increased the G1 phase ratio and decreased the S phase ratio in U87-MG cells. The western blotting results demonstrated that IDH1 R132H mutation decreased the expression levels of the S phase-associated proteins Cyclin A and CDK2, and increased the expression levels of the G1 phase-associated proteins Cyclin D3 and CDK4, but did not significantly change the expression levels of the G2/M phase-associated protein Cyclin B1. The expression levels of the positive and negative rhythm regulation genes BMAL1, CLOCK, period (PER s (PER1, 2 and 3) and cryptochrom (CRY)s (CRY1 and 2) were significantly decreased, those of the Smad signaling pathway-associated genes Smad2, Smad3 and Smad2-3 were decreased, and those of phosphorylated (p)-Smad2, p-Smad3 and Smad4 were increased. Therefore, the present results suggested that the IDH1 R132H mutation may alter the cell cycle and biological rhythm genes in U87-MG cells through the TGF-β/Smad signaling pathway.

The early discovery of covalent drugs is frequently inspired by, or derived from, natural sources, with such compounds often showing favorable safety profiles and a comparatively lower risk of clinical failure. However, a straightforward, high‐throughput technique for screening covalent‐binding molecules directly from complex medicinal plant extracts remains unavailable. In this study, we introduce an integrated strategy that combines protein microarrays with bioorthogonal click chemistry (Ccc‐Chip). This platform includes a differential scanning fluorimetry (DSF)‐based pre‐screening step to enhance efficiency, with the Ccc‐Chip serving as the core confirmation tool. It provides simple and intuitive readouts, enabling synchronous, high‐throughput screening of covalent ligands targeting multiple proteins through detection of their competitive binding with cysteine‐reactive probes. To validate the approach, we constructed a mutant isocitrate dehydrogenase 1 (mIDH1) protein microarray and used the integrated workflow to screen 110 medicinal plants. Our results led to the identification of flavokawain C (Flc), a covalent inhibitor of mIDH1, from Piper methysticum Forst. Subsequent in vivo experiments showed that Flc significantly reduced 2‐hydroxyglutarate (2‐HG) levels in an mIDH1‐driven orthotopic tumor model and enhanced CD8⁺ T cell activity. Notably, when combined with a programmed cell death protein 1 (PD‐1) blocking antibody, Flc synergistically augmented antitumor immunity, resulting in suppressed tumor growth. This work not only supports the high‐throughput utility of the Ccc‐Chip strategy but also provides a practical framework for combining bioorthogonal labeling with protein microarray technology, facilitating the discovery of bioactive covalent molecules from plant sources for challenging therapeutic targets. In this study, we develop a flexible Ccc‐Chip (protein microarray + bioorthogonal click chemistry) for high‐throughput screening of natural covalent active molecules from medicinal plant extracts, identifying flavokawain C from Piper methysticum Forst as a novel covalent mIDH1 inhibitor. Highlights Integrate and develop a bioorthogonal click chemistry‐protein chip platform for the label‐free and high‐throughput screening​ of covalent inhibitors directly from complex plant extracts. Flc as a covalent inhibitor of mIDH1 from 110 medicinal plant extracts; it significantly reduces the level of the oncogenic metabolite 2‐HG, and its combination with PD‐1 antibodies synergistically enhances anti‐tumor immunity. The platform is scalable, with flexibility for target proteins and specific probes, providing a solution with high sensitivity and specificity for mining covalent active molecules against refractory targets from natural medicinal plant sources.

Background/Objective: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with limited therapeutic options and poor survival outcomes. Recent advances in molecular oncology have highlighted the significance of isocitrate dehydrogenase 1 (IDH1) mutations as potential therapeutic targets. However, data on the prevalence and prognostic implications of IDH1 mutations in patients with iCCA are scarce. This study aimed to retrospectively investigate the IDH1 mutation rate, histopathological features, and survival outcomes of patients with iCCA. Methods: We retrospectively analyzed 88 patients diagnosed and treated between 2005 and 2025 at two tertiary oncology centers. Clinical, pathological, and survival data were obtained from the institutional oncology archives and national population databases. IDH1 mutation status was evaluated using polymerase chain reaction and next-generation sequencing of paraffin-embedded tissue samples. Results: A total of 88 patients with iCCA were included, with a median age of 62 years, and 62.5% were male. Abdominal pain was the most common presenting symptom (67%). The most frequent stages at diagnosis were stage IB and stage IIIB (22.7% each). Histopathologically, the small-duct subtype (55.7%), nodular morphology (67.0%), and solitary tumors (79.5%) predominated. IDH1 mutation was detected in 2.3% of patients. Curative surgery was performed in 78.2% of cases and was more common in early-stage disease. Gemcitabine–capecitabine was the most frequently used adjuvant regimen, whereas gemcitabine–cisplatin was the most common palliative treatment regimen. Median overall survival differed significantly by albumin-bilirubin (ALBI) grade, with 40.1, 11.1, and 4.4 months for grades 1, 2, and 3, respectively (p < 0.001). Conclusions: In this multicenter cohort, iCCA was characterized by diverse clinicopathological features and treatment approaches. Surgical resection remains the main treatment modality for patients with localized disease, whereas systemic therapies are more frequently used in advanced stages. The findings highlight the prognostic relevance of baseline clinical and biochemical characteristics and may improve risk stratification in patients with iCCA.

Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adults. Based on transcriptome profile, MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate dehydrogenase-1 and 2 ( IDH1 and IDH2 ) mutations have been described in several tumors, including gliomas, while in MB are rarely reported and not routinely investigated. By means of magnetic resonance spectroscopy (MRS), we unequivocally assessed the presence the oncometabolite D-2-hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutations, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also rarely described in MB. To the best of our knowledge, this is the first reported case of MB simultaneously harboring both mutations. Of note, tumor exhibited a heterogeneous phenotype with a tumor component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting co-existence of two different major tumor subclones. These findings drew attention to the need for a deeper genetic characterization of MB, in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, our results underlined the importance of performing MRS for the identification of IDH mutations in non-glial tumors. The use of throughput molecular profiling analysis and advanced medical imaging will certainly increase the frequency with which tumor entities with rare molecular alterations will be identified. Whether these findings have any specific therapeutic implications or prognostic relevance requires further investigations.

World Health Organization grade II and III gliomas most frequently occur in the central nervous system (CNS) in adults. Gliomas are not circumscribed; tumor edges are irregular and consist of tumor cells, normal brain tissue, and hyperplastic reactive glial cells. Therefore, the tumors are not fully resectable, resulting in recurrence, malignant progression, and eventual death. Approximately 69-80% of grade II and III gliomas harbor mutations in the isocitrate dehydrogenase 1 gene (IDH1), of which 83-90% are found to be the IDH1-R132H mutation. Detection of the IDH1-R132H mutation should help in the differential diagnosis of grade II and III gliomas from other types of CNS tumors and help determine the boundary between the tumor and normal brain tissue. In this study, we established a highly sensitive antibody-based device, referred to as the immuno-wall, to detect the IDH1-R132H mutation in gliomas. The immuno-wall causes an immunoreaction in microchannels fabricated using a photo-polymerizing polymer. This microdevice enables the analysis of the IDH1 status with a small sample within 15 min with substantially high sensitivity. Our results suggested that 10% content of the IDH1-R132H mutation in a sample of 0.33 μl volume, with 500 ng protein, or from 500 cells is theoretically sufficient for the analysis. The immuno-wall device will enable the rapid and highly sensitive detection of the IDH1-R132H mutation in routine clinical practice.

Acute myeloid leukemia (AML) harboring IDH1 mutations presents unique metabolic vulnerabilities that remain incompletely addressed by current targeted therapies. In this study, we demonstrate that IDH1-mutant AML cells are markedly more sensitive to cuproptosis induced by the copper ionophore elesclomol (ES), compared to their wild-type counterparts. While ES impairs mitochondrial function in both cell types, transcriptomic profiling reveals that ES treatment induces a global downregulation of lipid metabolism pathways. Functional assays further show that IDH1-mutant cells rely more heavily on exogenous fatty acids and exhibit impaired lipogenesis. Under lipid-deprived conditions, ES-induced cytotoxicity is significantly enhanced, suggesting a synthetic-lethal interaction between cuproptosis and fatty acid metabolic deficiency. experiments confirm that ES more effectively suppresses tumor growth in IDH1-mutant xenografts. These findings uncover a copper-dependent metabolic vulnerability and provide a rationale for exploiting cuproptosis as a therapeutic strategy in IDH1-mutant AML.

Periosteal chondroma is a benign cartilage tumor that accounts for <2% of chondromas. In the present study, four cases of periosteal chondromas were cytogenetically investigated and studied for the expression of high-mobility group AT-hook 2 (HMGA2), mutations in codons 132 of isocitrate dehydrogenase (IDH)1 and 172 of IDH2; mutations -C228T and -C250T in the promoter region of telomerase reverse transcriptase (TERT); and for methylation in the promoter regions of O-6-methylguanine-DNA methyltransferase (MGMT) and cellular retinol binding protein 1 (CRBP1). Chromosome aberrations of 12q13-15 were found in two out of the four tumors, while two had a normal karyotype. Two periosteal chondromas carried the mutation IDH1R132C (CGT>TGT), and two carried the mutation IDH1R132L (CGT>CTT). However, none of the four tumors had methylated MGMT and CRBP1 promoters or mutations at codon 172 of IDH2. In addition, -C228T and -C250T mutations were not present in the promoter region of TERT, nor was HMGA2 demonstrated to be expressed. The present study indicated that in periosteal chondromas, the involvement of 12q13-15 in structural rearrangements may be recurrent but that HMGA2 is not expressed. Additionally, the periosteal chondromas investigated in the study carried a heterozygous IDH1R132 mutation, the MGMT and CRBP1 promoters were not methylated, and -C228T and -C250T mutations in the promoter region of TERT were absent.