Glioblastoma (GBM), one of the most lethal human cancers, faces a major therapeutic challenge due to drug resistance. Temozolomide (TMZ), a standard first-line drug for clinical GBM treatment, benefits only a subset of patients, leaving an urgent need for strategies that can restore its efficacy. Herein, we propose that cuproptosis, a recently identified regulated cell death (RCD), is capable of reversing TMZ resistance in GBM. We design copper-TMZ (Cu-TMZ) prodrugs, assembled via the coordination of Cu2+ with TMZ and, in optimized formulations, co-loaded with metformin (MET) as an AMPK activator, to exploit cuproptosis for overcoming TMZ resistance. Upon glutathione-triggered disassembly, the prodrugs release Cu+ and TMZ, inducing mitochondrial proteotoxic stress and initiating a self-amplifying cuproptosis loop characterized by ATP depletion, AMPK-p53 activation, and glycolysis inhibition. Beyond self-reinforcement, cuproptosis directly potentiates TMZ activity by suppressing drug efflux, impairing DNA repair, and aggravating metabolic and redox stress. Both in vitro and in vivo experiments demonstrate that Cu-TMZ/MET prodrugs markedly restore TMZ responsiveness and suppress TMZ-resistant GBM progression. More broadly, this study illustrates how RCD pathways can be engineered into therapeutics to convert drug resistance into vulnerability, highlighting a generalizable strategy for improving the efficacy of frontline chemotherapy in otherwise intractable cancers.

Enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen of notable clinical concern due to its association with severe respiratory disease and the paralytic complication acute flaccid myelitis (AFM). Viral tropism and pathogenesis are critically dictated by interactions with host cell receptors. Our understanding of this process has evolved from a simple model of sialic acid dependence to a dynamic paradigm involving a repertoire of attachment factors and proteinaceous entry receptors. This review synthesizes the evolving landscape of EV-D68 receptor usage. We detail the well-established role of α2,6-linked sialic acid as an attachment factor and uncoating trigger for historical strains. We further discuss the discovery of intracellular adhesion molecule-5 (ICAM-5) as a neuron-specific receptor that provides a molecular explanation for neurotropism in AFM. A pivotal recent advance is the identification of major facilitator superfamily domain-containing 6 (MFSD6) as an essential entry receptor for a broad range of EV-D68 strains in both respiratory and neuronal cells. We explore the implications of this receptor versatility, whereby the virus can switch between or co-opt sialic acid, ICAM-5, and MFSD6, a plasticity that influences tissue tropism and viral evolution. Finally, we highlight how these mechanistic insights, particularly the characterization of the MFSD6 interface, are paving the way for novel therapeutic strategies, such as engineered decoy receptors, and outline key future directions in the field.

Glioma Amplified Sequence 41 (GAS41) is a chromatin-associated protein that belongs to the YEATS domain family of proteins and is frequently amplified in various tumors. However, its biological function and carcinogenic mechanism in gliomas are not fully understood. In this study, we revealed that GAS41 was upregulated in human glioma tissues and cell lines, and higher expression of GAS41 was significantly associated with poor clinical prognosis. Genetic depletion and chemical inhibition of GAS41 remarkably inhibited glioma cell proliferation and metastasis abilities and induced cellular apoptosis. Furthermore, functional annotation identified that GAS41 was involved in stimulating the expression of membrane protein ITGA4 to activate the downstream PI3K/Akt/mTOR signaling pathway in glioma cell lines. In addition, we synthesized and evaluated a series of small molecules targeting the GAS41 YEATS domain, which yielded effective anti-proliferative activities in glioma cells. Molecular docking revealed that these compounds bound to the GAS41 YEATS domain pocket in a manner similar to Compounds 9 and 3b, providing a structural basis for exploring the selective inhibition of GAS41 as part of an essential molecular framework. Overall, our study illustrates the crucial role of GAS41 in glioma progression and the malignant phenotype and suggests that targeting GAS41 may be a promising therapeutic treatment strategy for gliomas.

In the original publication [...].

Cuproptosis, a recently identified copper-dependent cell death modality, has opened a new territory in tumor therapy, which is promising to reverse the problem of chemoradiotherapy resistance due to its independence on the apoptotic mechanism. However, the inefficient promotion of copper influx and the intrinsic mechanism of copper efflux due to intracellular copper homeostasis significantly limit the efficacy of cuproptosis. Herein, we propose a strategy to disrupt copper homeostasis by designing copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs), which simultaneously promote copper influx and inhibit efflux, thereby leading to intense cuproptosis. On the one aspect, OME coordinates with copper ions to form self-delivery SNDs, facilitating the influx of copper ions. Under the glutathione stimulation of tumor microenvironment (TME), Cu-OME SNDs disassemble and release cuprous ions, which bind with mitochondrial acyltransferases to initiate cuproptosis. On the other aspect, the released OME inhibits copper efflux by suppressing ATPase copper transporting alpha expression, further enhancing copper dyshomeostasis and potentiating cuproptosis. A glioblastoma model is adopted to verify the cuproptosis efficacy of Cu-OME SNDs. To improve the permeability across blood-brain tumor barrier (BTB), minoxidil sulfate (MS) and T7 peptide are modified on Cu-OME SNDs to produce Cu-OME/MS@T7 SNDs. T7 peptide actively targets the transferrin receptor, facilitating the accumulation of SNDs in glioblastoma sites. MS, serving as a molecularly targeted ATP-sensitive potassium (KATP) modulator, selectively boosts BTB permeability. Upon entering glioblastoma cells, the released MS further activates KATP channels, promoting SNDs accumulation and establishing a positive feedback loop. Additionally, the cuproptosis induced by SNDs triggers immunogenic cell death in tumor cells, amplifying specific antitumor immunity and mitigating the immunosuppressive TME. Collectively, our findings demonstrate the effectiveness of OME-mediated nanodelivery of copper in inducing copper dyshomeostasis and triggering cuproptosis, highlighting their considerable therapeutic promise through synchronous remodeling of copper influx and efflux. Statement of Significance Cuproptosis has opened a promising frontier in tumor therapy. However, its efficacy is substantially hampered by the inefficient copper influx and the intrinsic copper efflux mechanism driven by intracellular copper homeostasis. To address these challenges, we propose a “two birds with one stone” strategy to disrupt copper homeostasis using copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs). In this design, OME coordinates with copper ions to form self-delivery SNDs, enhancing the delivery efficiency of exogenous copper ions. Meanwhile, the released OME further blocks copper efflux by suppressing ATP7A copper efflux transporter. Collectively, this work demonstrates the effectiveness of OME-mediated copper delivery in inducing copper dyshomeostasis and triggering cuproptosis, highlighting a promising therapeutic approach through synchronous remodeling of copper influx and efflux.

Temozolomide (TMZ) is an alkylating agent recommended as the first-line pharmaceutical for glioblastoma (GBM), but its efficacy is limited by the development of acquired resistance in GBM cells. TMZ resistance is regulated by multiple factors such as MGMT upregulation and metabolism reprogramming, its underlying mechanism still remains elusive. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor regulating the metabolism of lipid and glucose, while histone 3 lactylation at lysine on position 18 (H3K18la) could promote cancer cells’ resistance to therapeutic drugs. In this study we investigated the role of PPARα in regulating H3K18la and TMZ sensitivity in glioblastoma (GBM) cells. We established TMZ-resistant U87TR, U251TR, and U118TR cells by treating the parental U87, U251, and U118 cells with increased dosages of TMZ until the cells could resist TMZ (200 μM). We found that in TMZ-resistant cells, H3K18la level was apparently upregulated accompanied by increased ECAR (extracellular acidification rate) and intracellular lactate levels, whereas lactate (20 mM) time-dependently upregulated H3K18la in U87 and U251 cells. We found that PPARα was activated by TMZ in U87, U251, and U118 cells, but was inactivated when the cells became resistant to TMZ. In TMZ-sensitive glioma cells, TMZ triggered PPARα activation by causing DNA DSBs-dependent p38 MAPK activation. The activated PPARα upregulated its downstream signal ACOX1, which not only inhibited lactate-mediated H3K18 lactylation by promoting ROS-dependent PKM2 downregulation, but also reversely enhanced PPARα activation through ROS-activated ASK1/p38 MAPK pathway. In GBM cells resistant to TMZ, PPARα and p38 MAPK were both inactivated, but H3K18 lactylation was obviously upregulated. Targeting activation of PPARα with gemfibrozil or GW7647 not only sensitized GBM cells to TMZ but also effectively reversed the acquired resistance of GBM cells to TMZ by suppression of H3K18 lactylation through upregulation of ACOX1. Taken together, PPARα contributed to TMZ-induced growth arrest in GBM cells by inhibiting lactate-mediated H3K18 lactylation, targeting activation of PPARα may be a new strategy to improve the treatment effect of TMZ against GBM.

Shikonin (SHK), an active naphthoquinone pigment isolated from the root of Chinese herbal medicine has been proven to have a significant therapeutic effect on breast cancer. However, the poor water solubility as well as the lack of tumor targeting restrict the practice application of SHK molecules as chemotherapeutic agents. Here, SHK drugs were chemically conjugated to polyethylene glycol (PEG) molecules via a disulfide bond (referred to as SHK-SS-PEG) through a facile one-step strategy. The conjugates exhibited an excellent water solubility of 12.96 mM, which is ca. 7807 times as high as that of pure SHK drugs. Noteworthily, the conjugates can selfassemble into spherical micelles with an average particle size of 106 nm, facilitating in vivo delivery as well as the accumulation in tumor tissues based on the enhanced permeability and retention (EPR) effect. Moreover, the disulfide bond enables rapid cleavage of micelles and efficient release of SHK molecules from the conjugates in response to reduced Glutathione (GSH) overexpressed within tumor cells. Thanks to the GSH-responsiveness release of SHK, the conjugate-based micelles (containing 6 mu M SHK) resulted in the cell killing rate of 73 % for the MCF-7 breast cancer cells after 48 h incubation, which is 45 % higher than that for the HUVEC normal cells. All these collective beneficial properties make the SHK-SS-PEG conjugate a promising candidate for the treatment of many types of cancers.

As a novel lactate-derived post-translational modification, histone lactylation links metabolic reprogramming and epigenetic regulation in cancer. Histone lactylation, particularly at histone H3 lysine 18 lactylation (H3K18la), has been implicated in tumor initiation, progression, metastasis, immune evasion and therapy resistance. It modulates oncogenic pathways (such as PI3K/Akt/mTOR, NF-κB, JAK/STAT) and metabolic pathways (such as glycolysis enhancement, fatty acid synthesis via stearoyl-CoA desaturase and glutamine metabolism) and by altering chromatin structure and gene transcription. In the tumor microenvironment, lactate-induced H3K18la polarizes macrophages toward an M2 phenotype, upregulates immune checkpoints and induces CD8+ T cells dysfunction, which promotes immunosuppression. However, CD8+ T cell-intrinsic lactylation may enhance antitumor immunity during checkpoint blockade. Histone lactylation also induces chemoresistance via autophagy activation, DNA repair and ferroptosis suppression. Therapeutic strategies targeting lactylation include inhibiting lactate transporters, glycolysis or regulation enzymes (such as E1A-binding protein, lysine acetyltransferase 2A and brahma-related gene 1). Furthermore, the clinical potential is emerging, with H3K18la and H4K5la serving as prognostic biomarkers in multiple types of cancer. However, key questions regarding the non-enzymatic modification mechanisms, identification of histone lactation regulatory enzymes and pan-cancer functional heterogeneity are yet to be elucidated. Future research should prioritize translational validation of lactylation-targeted therapies and their integration with existing regimens to overcome resistance and improve immunotherapy efficacy.

Clear cell meningiomas are a rare histological subtype of World Health Organization (WHO) grade II meningioma. Despite its relatively low frequency, clear cell meningioma has attracted considerable attention because of its unique pathological characteristics, clinical behavior, and challenging management considerations. The purpose of our systematic review is to provide clinicians with a better understanding of this rare disease. PubMed was searched for articles in the English language published from 1988 to 2023 June. The keywords were as follows: “clear cell meningioma,” “clear cell” and “meningioma.” We analyzed clinical manifestations, radiological manifestations, pathological features, comprehensive treatment strategies, and prognosis to determine the factors influencing recurrence-free survival (RFS). Recurrence-free survival curves of related factors were calculated by the Kaplan‒Meier method. The log-rank test and Cox univariate analysis were adopted to assess the intergroup differences and seek significant factors influencing prognosis and recurrence. Fifty-seven papers met the eligibility criteria, including 207 cases of clear cell meningioma (CCM), which were confirmed by postoperative pathology. The fifty-seven articles involved 84 (40.6

Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 is an enzyme accounting for removing acetylated lysine residues from target proteins by consuming NAD+, but its role remains elusive in ferroptosis and activating ATF3. In this study, we found SIRT1 was activated during the process of RSL3-induced glioma cell ferroptosis. Moreover, the glioma cell death was aggravated by SIRT1 activator SRT2183, but suppressed by SIRT inhibitor EX527 or when SIRT1 was silenced with siRNA. These indicated SIRT1 sensitized glioma cells to ferroptosis. Furthermore, we found SIRT1 promoted RSL3-induced expressional upregulation and nuclear translocation of ATF3. Silence of ATF3 with siRNA attenuated RSL3-induced increases of ferrous iron and lipid peroxidation, downregulation of SLC7A11 and GPX4 and depletion of cysteine and GSH. Thus, SIRT1 promoted glioma cell ferroptosis by inducting ATF3 activation. Mechanistically, ATF3 activation was reinforced when RSL3-induced decline of NAD+ was aggravated by FK866 that could inhibit NAD + synthesis via salvage pathway, but suppressed when intracellular NAD+ was maintained at higher level by supplement of exogenous NAD+. Notably, the NAD + decline caused by RSL3 was enhanced when SIRT1 was further activated by SRT2183, but attenuated when SIRT1 activation was inhibited by EX527. These indicated SIRT1 promoted ATF3 activation via consumption of NAD+. Finally, we found RSL3 activated SIRT1 by inducing reactive oxygen species-dependent upregulation of AROS. Together, our study revealed SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via activation of ATF3-dependent inhibition of SLC7A11 and GPX4.

BACKGROUND:Copper is an essential trace element for biological systems, as it plays a critical role in the activity of various enzymes and metabolic processes. However, the dysregulation of copper homeostasis is closely associated with the onset and progression of numerous diseases. In recent years, copper-induced cell death, a novel form of cellular demise, has garnered significant attention. This process is characterized by the abnormal accumulation of intracellular copper ions, leading to cellular dysfunction and eventual cell death. Copper toxicity occurs through the interaction of copper with acylated enzymes in the tricarboxylic acid (TCA) cycle. This interaction results in subsequent protein aggregation, causing proteotoxic stress and ultimately resulting in cell death. Despite the promise of these findings, the detailed mechanisms and broader implications of cuproptosis remain underexplored. Therefore, our study aimed to investigate the role of copper in cell death and autophagy, focusing on the molecular mechanisms of cuproptosis. We also aimed to discuss recent advancements in copper-related research across various diseases and tumors, providing insights for future studies and potential therapeutic applications. MAIN BODY:This review delves into the biological significance of copper metabolism and the molecular mechanisms underlying copper-induced cell death. Furthermore, we discuss the role of copper toxicity in the pathogenesis of various diseases, emphasizing recent advancements in the field of oncology. Additionally, we explore the therapeutic potential of targeting copper toxicity. CONCLUSION:The study highlights the need for further research to explore alternative pathways of copper-induced cell death, detailed mechanisms of cuproptosis, and biomarkers for copper poisoning. Future research should focus on exploring the molecular mechanisms of cuproptosis, developing new therapeutic strategies, and verifying their safety and efficacy in clinical trials.

The authors regret that they divided the blots from the same groups of samples into two images (Fig. 4 C and 4D) in consideration of layout neatness but used the same beta -actin. Although Fig. 4 C and D were both from the same group of samples, it is not properly to use the same beta -actin in Fig. 4 C and 4D. Similar blot division and usage of the same beta -actin could also be found in Fig 5B and 5C. The authors would like to merge figure Fig. 4C and D into one image, and merge figure Fig.5B and 5C into one image. Thus, they make this corrigendum.

Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herb Anthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 μmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 μmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+ levels in U87 and U251 cells. Further decrease of NAD+ levels with FK866 (100 μmol/L) aggravated, but supplement of NAD+ (0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+ depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+ depletion-dependent upregulation of NOX2 and NAT10.

Maltol, a chemical isolated from ginseng root, has shown treatment effects on several pathological processes including osteoarthritis, diabetic peripheral neuropathy and liver fibrosis. Nevertheless, its effect on ischemia-induced neuron death remains elusive. In the present study, the treatment effect of maltol on ischemia-induced neuron damage was investigated by using oxygen and glucose deprivation (OGD) model in SH-SY5Y cells. In vitro studies revealed that maltol protected SH-SY5Y cells against OGD-induced chromatinolysis by inhibiting two reactive oxygen species (ROS)-regulated pathways. One was DNA double-strand breaks and the other was nuclear translocation of apoptosis inducing factor. Mechanistically, maltol not only inhibited OGD-induced depletion of glutathione and cysteine by maintaining cystine/glutamate antiporter (xCT) level, but also abrogated OGD-induced catalase downregulation. Meanwhile, maltol also alleviated OGD-induced inactivation of mTOR by attenuating OGD-induced depletion of adenosine triphosphate and pyruvate and downregulation of pyruvate kinase M2, indicating that maltol inhibited the glycolysis dysfunction caused by OGD. Considering that activated mammalian target of the rapamycin (mTOR) could lead to enhanced xCT expression and decreased catalase degradation by autophagy, these findings indicated that maltol attenuated OGD-induced ROS via inhibition of mTOR inactivation by maintaining pyruvate level. Taken together, it was demonstrated that maltol prevented OGD-induced chromatinolysis in SH-SY5Y cells via inhibiting pyruvate depletion.

Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD+). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg−1 ·d−1, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD+ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR.

AIMS:Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1), excessive synthesis of poly ADP-ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure-induced hippocampal neuronal death.METHODS:Glutamate-mediated excitotoxicity cell model was used to study the mechanism of seizure-induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments.RESULTS:In vitro, glutamate time-dependently induced HT22 cell death, accompanied by parthanatos-related biochemical events. Pretreatment with PJ34 (PARP-1 inhibitor) or small interfering RNA-mediated PARP-1 knockdown effectively protected HT22 cells against glutamate-induced toxic effects and attenuated parthanatos-related biochemical events. Application of the antioxidant N-acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos-related biochemical events. In vivo, PJ34 and NAC afforded protection against SE-induced hippocampal neuronal damage and inhibited parthanatos-related biochemical events.CONCLUSION:Parthanatos participates in glutamate-induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.