HyeSook Youn

Background Glioblastoma (GBM) is an aggressive brain tumor characterized by a poor prognosis and resistance to radiotherapy. Although multiple mechanisms of radioresistance have been proposed, the contribution of membrane-driven metabolic adaptations to radioresistance remains poorly understood. Methods The role of UDP-glucose ceramide glucosyltransferase (UGCG) was investigated using radioresistant GBM cell lines and in vivo xenograft models. After inhibiting UGCG function through genetic or pharmacological (miglustat) approaches, we assessed the effects on lipid raft integrity, localization of the ASCT2 transporter, glutamine uptake, oxidative stress, and radiosensitivity. Results UGCG was upregulated in radioresistant GBM cells and promoted lipid raft stabilization. This facilitated the membrane recruitment of the glutamine transporter ASCT2 (SLC1A5), thereby sustaining redox homeostasis under radiation stress. Genetic or pharmacological inhibition of UGCG disrupted lipid raft integrity, impaired ASCT2 localization, reduced glutamine uptake, and increased oxidative stress, leading to enhanced radiosensitivity. In GBM xenograft models, UGCG inhibition combined with radiotherapy significantly suppressed tumor growth and extended survival. Conclusions These findings reveal a previously underexplored, membrane-centric mechanism of radioresistance in which UGCG orchestrates lipid raft remodeling to facilitate glutamine-dependent redox balance. This highlights UGCG as a potential therapeutic target to enhance the efficacy of radiotherapy in GBM.

Cancer stem cells (CSCs) are a highly plastic subpopulation of tumor cells with capabilities for self-renewal, therapy resistance, and metastasis. Recent evidence highlights lipid metabolic reprogramming as a central mechanism supporting these malignant traits. This review synthesizes current findings on key lipid metabolic processes in CSCs—including lipid uptake via CD36, intracellular storage in lipid droplets, de novo fatty acid synthesis by fatty acid synthase (FASN), fatty acid oxidation (FAO) regulated by carnitine palmitoyltransferase 1A (CPT1A), and cholesterol biosynthesis through the mevalonate pathway. Although many of these pathways are active in bulk cancer cells, CSCs demonstrate greater functional reliance on them, leading to enhanced survival, redox balance, and adaptation to therapy. These metabolic preferences vary by cancer type, underscoring the need for context-specific approaches. Moreover, stromal components of the tumor microenvironment (TME), such as cancer-associated fibroblasts, adipocytes, and mesenchymal stem cells, modulate CSC lipid metabolism through paracrine signals and substrate transfer, reinforcing CSC maintenance and drug resistance. Therapeutic strategies targeting lipid metabolism—such as inhibition of SCD1, CPT1A, and HMG-CoA reductase—have shown promising preclinical results in selectively depleting CSC populations and sensitizing tumors to treatment. However, challenges remain in preserving normal stem cell function, which also depends on lipid pathways. This review underscores the emerging significance of lipid metabolism as both a hallmark and vulnerability of CSCs, offering opportunities for novel targeted cancer therapies.

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that interact with the estrogen receptor (ER), thereby disrupting estrogen-mediated signaling. In a previous study, we employed a bioluminescence resonance energy transfer (BRET) system to assess ER dimerization for detecting EDCs. To further determine whether the BRET assay could be used independently to identify EDCs, we investigated ER-EDC interactions before and after dimerization. Results from isothermal titration calorimetry (ITC) and dynamic light scattering (DLS) revealed that ER dimerization can be mediated by EDCs. Consequently, the BRET assay proved effective in detecting dimerization and clarifying its relevance to EDC-induced signaling disruption. Additionally, to examine EDC-induced transcriptional changes, we performed chromatin immunoprecipitation sequencing (ChIP-seq), followed by gene ontology (GO) analysis. These analyses demonstrated that EDCs affect various signaling pathways, including those involved in antibody-dependent cytotoxicity, bone morphogenetic protein (BMP) signaling in cardiac induction, and hepatocyte growth factor receptor signaling. Overall, this study elucidates the molecular mechanisms by which EDCs influence ER dimerization and signaling. These findings highlight the utility of the BRET-based assay for EDC detection and contribute to a deeper understanding of the systemic effects of EDCs on endocrine disruption.

Inthe present study, we fabricated hollow cubic Cu (x) O nanoparticles (& SIM;23 nm) incorporatedwithCNF (HC-Cu (x) O/CNF) through controlled thermaloxidation of solid cubic Cu2O nanoparticles (& SIM;21nm) supported on carbon nanofibers (SC-Cu2O/CNF) underairflow, exploiting the nanoscale Kirkendall effect. These hollowCu (x) O nanocubes with increased surfaceareas exhibited outstanding catalytic activity for unsymmetrical chalcogenidesynthesis under ligand-free conditions. SolidCu(2)O cubes/CNF are synthesized and subsequentlytransformed to hollow Cu (x) O cubes/CNF bythe thermal oxidation process, adopting the Kirkendall effect. Theresulting HC-Cu (x) O/CNF with increased surfacearea are highly efficient for the synthesis of unsymmetrical chalcogenidesin excellent yields under ligand-free conditions.

Shikonin, a natural ingredient produced by Lithospermum erythrorhizon, has anti-inflammatory, anti-cancer, and anti-obesity effects. It also inhibits adipocyte differentiation; however, the underlying molecular and epigenetic mechanisms remain unclear. We performed RNA-sequencing of shikonin-treated 3T3-L1 cells. Gene ontology and gene set enrichment analysis showed that shikonin is significantly associated with genes related to adipogenesis, histone modification, and PPARγ. Shikonin treatment downregulated the mRNA expression of PPARγ-responsive genes and rosiglitazone-induced transcriptional activity of PPARγ. Microscale thermophoresis assays showed a K_D value 1.4 ± 0.13 μM for binding between shikonin and PPARγ. Glutathione S-transferase pull-down assays exhibited that shikonin blocked the rosiglitazone-dependent association of PPARγ with its coactivator CBP. In addition, shikonin decreased the enrichment of the active histone code H3K4me3 and increased the repressive code H3K27me3 of PPARγ target promoters. Shikonin is a PPARγ antagonist that suppresses adipogenesis by regulating the enrichment of histone codes during adipogenesis. Therefore, it may be used to treat obesity-related disorders via epigenetic changes.

Atherosclerosis is a lipid-driven chronic inflammatory disease that causes cardiovascular diseases (CVD). The association between radiation and atherosclerosis has already been demonstrated; howeve...

Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)—a positive regulator of the autophagy initiation step—was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine—a vasodilator agent discovered through drug repositioning—significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.

Cancer cachexia is a muscle-wasting syndrome that leads to a severely compromised quality of life and increased mortality. A strong association between cachexia and poor prognosis has been demonstrated in intractable cancers, including glioblastoma (GBM). In the present study, it was demonstrated that ionizing radiation (IR), the first-line treatment for GBM, causes cancer cachexia by increasing the exosomal release of plasminogen activator inhibitor-1 (PAI-1) from glioblastoma cells. Exosomal PAI-1 delivered to the skeletal muscle is directly penetrated in the muscles and phosphorylates STAT3 to intensify muscle atrophy by activating muscle RING-finger protein-1 (MuRF1) and muscle atrophy F-box (Atrogin1); furthermore, it hampers muscle protein synthesis by inhibiting mTOR signaling. Additionally, pharmacological inhibition of PAI-1 by TM5441 inhibited muscle atrophy and rescued muscle protein synthesis, thereby providing survival benefits in a GBM orthotopic xenograft mouse model. In summary, our data delineated the role of PAI-1 in the induction of GBM cachexia associated with radiotherapy-treated GBM. Our data also indicated that targeting PAI-1 could serve as an attractive strategy for the management of GBM following radiotherapy, which would lead to a considerable improvement in the quality of life of GBM patients undergoing radiotherapy.