Glioblastoma (GB) is characterized by aggressive progression and frequent recurrence despite temozolomide (TMZ)-based therapy. Although resistance is commonly linked to DNA repair mechanisms, these pathways do not fully explain tumor persistence under therapeutic stress. Accumulating evidence suggests that metabolic reprogramming, particularly crosstalk between lipid metabolism and autophagy, may contribute to GB adaptation under TMZ-induced stress. We discuss how this lipid-autophagy interface may enable tumor cells to reconfigure energy production, maintain redox balance, and remodel membranes in response to therapy. Although the available evidence remains predominantly preclinical, convergent findings from lipidomic analyses and functional perturbation studies support lipid-autophagy crosstalk as an emerging contributor to TMZ resistance. This review presents this interaction as a testable conceptual framework for understanding metabolic adaptation to TMZ and discusses its potential therapeutic relevance.

Temozolomide (TMZ) is widely used in aggressive cancers, but its efficacy may be limited by tumor DNA repair mechanisms. Inhibition of PARP with veliparib (ABT-888) has been proposed to enhance TMZ-induced cytotoxicity. We conducted this systematic review and meta-analysis to evaluate the efficacy of this combination on overall survival (OS) and progression-free survival (PFS) in patients with cancer. PubMed, Scopus, CENTRAL, and ClinicalTrials.gov were systematically searched up to August 2026, using predefined terms. Eligible studies were phase II and III randomized controlled trials (RCTs) evaluating PFS and OS of veliparib combined with temozolomide versus control therapy. Random-effects models with restricted maximum-likelihood (REML) estimation with Hartung-Knapp (HK) adjustment were applied. Statistical analyses were performed with R with significance set at P<0.05. Certainty of evidence was assessed using the GRADE framework. From 729 records screened, 4 RCTs enrolling 1022 patients were included. No statistically significant improvement was shown in OS (HR=0.94, 95% CI: 0.78-1.13, I2=0.0) or PFS (HR=0.88, 95% CI: 0.71-1.08, I2=25.5). Subgroup analyses for OS similarly showed no statistically significant benefit. This meta-analysis did not demonstrate a statistically significant OS and PFS benefit from veliparib plus temozolomide compared with control therapy. This finding should be interpreted cautiously. The certainty of evidence was rated as moderate for both OS and PFS according to GRADE. Future studies should focus on biomarker-driven approaches and optimized dosing strategies to better define the clinical utility of this regimen.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor, with a median survival of approximately 15 months despite current multimodal therapies. Recent clinical observations have suggested that the intravenous anesthetic propofol may be used to examine whether anesthetic agents can affect glioblastoma behavior. Several retrospective studies reported that, in surgical settings, propofol-based total intravenous anesthesia (TIVA) is associated with reduced operative time, faster recovery, lower intraoperative blood loss, and decreased postoperative complications such as seizures and cerebral edema, benefits particularly evident in patients with low Karnofsky Performance Scores. However, current clinical evidence remains limited, and the reported effects on survival and recurrence are still inconsistent. Preclinical studies showed that propofol's antitumor potential is mediated through modulation of the PI3K/AKT-Wnt-miRNA axis, reduction of oxidative stress, regulation of immune checkpoint molecules, and restoration of temozolomide sensitivity in resistant cells. However, some reports indicate that propofol may also induce stem-like features via GABA-A receptor activation, underscoring its complex and context-dependent nature. This narrative review summarizes the current molecular and clinical evidence about propofol in GBM. Available laboratory and retrospective clinical studies indicate possible antitumor effects, but the present evidence does not support definitive clinical conclusions. Large prospective and multicenter studies are still needed to clarify the clinical role of propofol in patients with GBM.

Gliomas remain among the most lethal brain tumours, driven by aggressive invasion, stem-like properties, metabolic plasticity, and frequent resistance to temozolomide (TMZ). Hypoxia-inducible factor-1α (HIF-1α) is a central regulator of these malignant traits. In this study, we identify methyl 4-O-demethylbarbatate (Me-4-O-DBA), a biosynthetically produced lichen-derived metabolite, as a potential modulator of HIF-1α signaling. Molecular docking analysis suggested a possible interaction between Me-4-O-DBA and HIF-1α near the Lys304 ubiquitination site, which may contribute to reduced HIF-1α stability and suppression of downstream EMT and stemness signaling. This inhibition simultaneously attenuated both glycolytic activity and mitochondrial respiration, indicating a broad suppression of metabolic reprogramming. Network pharmacology and molecular docking further indicated HIF-1α-associated signaling as a potential regulatory hub, while in vitro assays demonstrated marked reductions in glioma cell viability, invasion, migration, and clonogenicity. Notably, Me-4-O-DBA synergised with TMZ to enhance suppression of motility, stemness, and metabolic activity, resulting in profound impairment of tumourigenic potential. In vivo zebrafish assays also indicated a favourable safety profile at the tested concentrations. Together, these findings suggest that Me-4-O-DBA suppresses HIF-1α-associated malignant phenotypes and enhances TMZ responsiveness in glioma cells, highlighting its potential as a natural product-derived modulator of glioma progression.

Lipid nanoparticles (LNPs) are the leading non-viral platform for nucleic acid delivery, and the structural design of ionizable lipids critically determines their delivery efficiency and therapeutic potential. Here, a dual-functional ionizable lipid was developed by integrating a vinpocetine-derived neurovascular regulatory motif with the chemotherapeutic agent temozolomide (TMZ), enabling the construction of a brain-directed lipid nanoparticle platform termed TVP. Compared with the clinically used MC3-based LNPs, TVP significantly enhanced cerebral blood perfusion and exhibited superior brain accumulation in both healthy mice and orthotopic glioma-bearing mice. In addition to improved brain delivery, TVP promoted selective glioma localization and exerted intrinsic anti-glioma activity, while efficiently supporting nucleic acid cargo delivery. When co-loaded with therapeutic nucleic acids, the TVP system achieved potent inhibition of glioma progression through synergistic neurovascular targeting, chemotherapy, and gene intervention, while maintaining favorable biosafety. These findings establish TVP as a multifunctional brain-directed LNP platform and provide a promising strategy for overcoming delivery barriers in glioma therapy.

Acquired resistance to temozolomide (TMZ) remains a major therapeutic challenge in glioblastoma (GBM), with metabolic reprogramming emerging as a critical driver of treatment failure. Procollagen lysyl hydroxylase 1 (PLOD1) is identified as a key regulator of adaptive metabolic remodeling in TMZ-resistant GBM. Elevated PLOD1 promotes a hyper-glycolytic phenotype by maintaining the stability of the glycolytic enzyme alpha-enolase (ENO1). Mechanistically, PLOD1 catalytic activity increases an ENO1-associated hydroxylation signal, promotes ENO1 stability, and limits FBXW7-dependent ubiquitination and proteasomal degradation. Structural and functional analyses reveal that the central Ndst region of PLOD1 mediates substrate interaction, whereas its catalytic domain is required for ENO1 stabilization and downstream metabolic regulation. Clinically, PLOD1 and ENO1 expression levels are positively correlated in GBM specimens, and their co-expression is associated with unfavorable patient outcomes. In xenograft models, inhibition of the PLOD1-ENO1 axis suppresses tumor progression and enhances TMZ responsiveness. These findings establish the PLOD1-FBXW7-ENO1 regulatory axis as a critical mediator of GBM metabolic adaptation and therapeutic resistance, highlighting its potential as a prognostic biomarker and therapeutic target.

The treatment landscape for metastatic uterine leiomyosarcoma has expanded in recent years with the introduction of newer chemotherapeutic and targeted therapies; however, effective treatment options remain limited. We present the case of a woman in her early 60s with metastatic uterine leiomyosarcoma who had received five lines of therapy for metastatic disease. She was subsequently treated with rucaparib 400 mg twice daily on days one through seven of a 28-day cycle and temozolomide 120 mg once daily on days one through seven of the same cycle, with subsequent dose reduction of both agents because of hematological toxicity. After three months of treatment, she achieved a complete metabolic response on fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). After eight months of treatment, she developed progressive disease. Next-generation sequencing for the homologous recombination repair deficiency panel was attempted but was unsuccessful because of degraded DNA; therefore, her homologous recombination deficiency status could not be confirmed. This case describes clinical activity with rucaparib plus temozolomide in a heavily pretreated patient with advanced uterine leiomyosarcoma and highlights the need for further investigation of this therapeutic approach.

BACKGROUND: Chemoimmunotherapy (ChIt) has been proven to be an effective treatment for patients with refractory high-risk neuroblastoma (HR-NBL). The objective was to assess the appearance of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) in patients previously treated with ChIt for refractory HR-NBL. METHODS: Nineteen patients were treated with ChIt based on dinutuximab beta for refractory NBL and underwent ASCT. Six patients underwent HDC with ASCT according to the SIOPEN protocol (Busulfan and Melphalan (BuMel)). Treosulfan and Melphalan (TreoMel) were used in 13 patients. The occurrence of VOD/SOS was analysed. The Mann-Whitney U test was used to analyse the correlation between VOD/SOS and potential risk factors. RESULTS: VOD/SOS developed in five out of six patients when BuMel was used after ChIt (3 pts, grade 4; 2 pts, grade 3), resulting in two deaths. No VOD/SOS was observed in patients receiving TreoMel. Other analysed factors had no influence of VOD/SOS occurrence and the only identified risk factor was BuMel administered after ChIt. CONCLUSIONS: Patients with refractory HR-NBL treated with ChIt and DB did not present life-threatening toxicities or severe liver toxicities during the ChIt cycles and continued to HDC with ASCT according to SIOPEN guidelines. The incidence of severe VOD/SOS after ChIt and subsequent BuMel was higher than expected, with severe course resulting in two deaths. Taking into account the possible increase in the risk of VOD/SOS after BuMel used after chemotherapy combined with DB, careful observation with early VOD/SOS treatment in patients after ChIt is recommended and TreoMel regimen may be considered as less toxic.

Highly aggressive gliomas remain difficult to treat because of their marked invasiveness, frequent recurrence, and association with glioma-related epilepsy. Increasing evidence suggests that ion channels expressed in glioma cells, including voltage-gated Na[+] channels, large-conductance Ca[2+]-activated K[+] (BKCa) channels, intermediate-conductance Ca[2+]-activated K[+] (IKCa) channels, and inwardly rectifying K[+] (Kir) channels, contribute to these malignant phenotypes and represent potential therapeutic targets. This perspective summarizes current evidence for eight representative drugs and phytoconstituents-perampanel, valproic acid, cilostazol, berberine, oxaliplatin, temozolomide, arecoline, and triptolide-that modulate these ion channels. Perampanel and valproic acid suppress voltage-gated Na[+] current in glioma cells and may provide additional benefits in controlling glioma-associated epilepsy. Cilostazol activates BKCa channels, whereas berberine, oxaliplatin, and temozolomide inhibit IKCa channel activity. Arecoline suppresses IKCa and Kir channel activity, while triptolide inhibits Kir channels. These observations suggest that ion channel modulation may influence glioma cell proliferation, migration, invasion, and excitability. To complement the available experimental evidence, we performed molecular docking analyses as a hypothesis-generating approach to explore potential ligand-channel interactions. Because these computational predictions have not been experimentally validated, they should be interpreted cautiously and viewed as a framework for future mechanistic studies rather than definitive evidence of binding. We also discuss important translational considerations, including the limited clinical evidence and the toxicity profiles of several compounds. In particular, arecoline is associated with carcinogenicity and neurotoxicity, triptolide with significant systemic toxicity, berberine with poor oral bioavailability and potential drug interactions, and oxaliplatin with dose-limiting neurotoxicity. Overall, this perspective highlights ion channels as promising therapeutic targets in glioma while emphasizing the need for rigorous experimental validation and careful evaluation of safety before clinical translation.

Glioblastoma (GBM) standard of care includes surgical resection followed by ionizing radiation (IR) and Temozolomide, which induce DNA double-strand breaks. Homologous recombination (HR), a critical DNA double-strand break repair pathway, is augmented in GBM, contributing to resistance and poor patient outcomes. Here, we demonstrate that increasing deoxyribonucleoside triphosphate (dNTP) levels impairs HR-mediated double-strand break repair, rendering GBM cells sensitive to IR and Temozolomide. Interestingly, combining an elevated dNTP pool level with IR and/or Temozolomide promotes the recruitment of DNA polymerase-α/primase, which is typically involved in Okazaki fragment synthesis during DNA replication, to the DNA double-strand break site, thereby interfering with DNA end resection. Specifically, higher dNTP pool levels disrupted the recruitment of HR-associated proteins such as RPA70 and RAD51, an effect reversed by Aphidicolin, a DNA polymerase-α/primase inhibitor. Impaired HR delayed IR- and/or Temozolomide-induced DNA double-strand break repair, leading to growth arrest and apoptosis. Furthermore, higher dNTP pool levels led to downregulation of DNA replication and HR-associated genes, while upregulating several pro-apoptotic genes. Increased sensitivity to IR and Temozolomide was also observed in engineered IR-resistant GBM cell lines and in naturally recurrent patient-derived GBM cells that emerge post-therapy. These findings emphasize how dNTP pool levels regulate HR and uncover a promising vulnerability that could be exploited to overcome resistance to DNA-damaging treatments in GBM and beyond.

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor characterized by dysregulated cellular signaling and resistance to apoptosis. Pulsed electromagnetic field (PEMF) exposure has been reported to modulate cancer-related cellular processes, while resveratrol (RES), a natural polyphenol, exhibits notable antiproliferative and pro-apoptotic actions. Here, we investigated whether 75 Hz PEMF potentiates RES-mediated apoptosis in human glioblastoma U87-MG cells by examining key molecules involved in apoptotic signaling and the transcriptional responses of PI3K/AKT/mTOR pathway-related genes. U87-MG glioblastoma cells and non-tumour human astroglial SVG-P12 cells were cultured and divided into the following six groups: (I) untreated cells; (II) RES-treated cells; (III) temozolomide (TMZ)-treated cells; (IV) PEMF-exposed cells; (V) cells treated with RES followed by PEMF exposure; and (VI) cells treated with TMZ followed by PEMF exposure. Cell viability was assessed in both cell lines by alamar blue assay, and selectivity indices were derived from the resulting IC50 values. Apoptotic responses and gene expression profiles were assessed in U87-MG cells by flow cytometry and qRT-PCR, while selected apoptosis-related proteins were evaluated by Western blotting. RES treatment induced stronger cytotoxic effects than TMZ in U87-MG cells, and this response was markedly enhanced following PEMF exposure, the IC50 falling from 33.64 to 10.53 µg/mL. In SVG-P12 astroglia the IC50 of RES rose from 17.95 to 98.31 µg/mL under the same exposure, so that the selectivity index of RES increased from 0.53 to 9.34, whereas that of TMZ remained essentially unchanged (1.54 versus 1.50). Combined RES and PEMF treatment significantly increased both early and late apoptosis. Molecular analyses revealed upregulation of pro-apoptotic markers accompanied by an increased Bax/BcL-2 ratio, consistent with protein-level changes. Transcripts of PI3K/AKT/mTOR pathway-related components were also elevated relative to untreated cells, but to a markedly lesser extent than the apoptotic markers. PEMF exposure significantly enhances the pro-apoptotic effects of RES in glioblastoma cells while relatively preserving SVG-P12 cell viability, supporting further investigation of this combination as a potential adjuvant approach.

Adult brainstem gliomas (BSGs) are rare malignant tumors of the central nervous system (CNS) that are difficult to resect completely via surgery, so chemoradiotherapy (CRT) is the primary treatment modality. However, there is substantial interpatient variability in therapeutic response to CRT among patients with BSGs. Here we present a case of a 41-year-old man who had experienced right limb weakness for 3 months. Brain MRI showed a solid-cystic mass in the brainstem, involving the medulla oblongata and the cervical spinal cord. The pathological diagnosis was pilocytic astrocytoma, CNS WHO Grade 1. Since the solid-cystic mass in the brainstem was unresectable, the patient received concurrent CRT followed by temozolomide (TMZ) maintenance chemotherapy. No significant change in tumor size was observed after concurrent CRT. Notably, 15 months after radiotherapy (19 months since the initial diagnosis), the tumor size decreased significantly. Up to the latest follow-up, the patient has maintained sustained partial remission.

Background: Glioblastoma is highly heterogeneous, highly invasive, and resistant to temozolomide, with an extremely low 5-year survival rate. The spatial association between polyamine metabolism and ferroptosis remains unclear. Spatial metabolic heterogeneity is a core challenge in glioblastoma treatment. Methods: In this study, 17 patients with primary or recurrent high-grade glioma were included. Spatial metabolomics (n = 9), multiplex immunofluorescence (exploratory experiment n = 10, observational experiment n = 1), flow cytometry (n = 13), and mouse orthotopic models (n = 3) were combined to analyze the characteristics of the polyamine-ferroptosis axis in the para-carcinoma, tumor, and necrotic regions. Results: Differences in the polyamine-metabolism-ferroptosis axis were observed across distinct pathological regions of glioblastoma. Regional differences in polyamine distribution were associated with regional differences that lower lipid-peroxidation signals in the tumor region and higher lipid-peroxidation signals in the necrotic region. Moreover, in glioblastoma patient specimens, lipid-peroxidation-associated signals were detected in immune-cell compartments, alongside immune-cell phenotypic features suggestive of dysfunction, which show correlation with an immunosuppressive microenvironment. At the regional level, enzymes related to polyamine metabolism, namely GLS and SMS, exhibited spatial co-localization trends with lipid-peroxidation markers. Alterations in markers of the GSH-GPX4 and FSP1 antioxidant systems were spatially associated with the tumor-region-specific lipid-peroxidation profile. Partial spatial patterns of polyamine metabolism observed in human samples were partially recapitulated in mouse orthotopic tumor models. Conclusions: Glioblastoma exhibits spatially distinct distribution of the polyamine-ferroptosis-associated molecular signature. Notable correlative spatial features include spermidine and spermine enrichment, altered regional abundance within the glutamine-glutamate metabolic axis, immune-cell lipid-peroxidation-associated signals and immune-cell-dysfunction-related phenotypes, and regional shifts in GSH-GPX4/FSP1-related markers. This study identifies potential targets and provides a correlative spatial framework for region-specific therapeutic investigation, but the establishment of the causal relationship still requires further functional verification.