KYNU can promote GC proliferation, invasion, metastasis, and cuproptosis resistance.This effect is not associated with its metabolite 3-HA, but is achieved by a non classical mechanisms that downregulating the expression of LIAS, a key gene of cuproptosis.

Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model. Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis via circFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.

The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC)...Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.

Moreover, we observed a positive correlation between sample immune infiltration and sample resistance to elesclomol and panobinostat, whereas a negative correlation was found with venetoclax resistance. Our study enriches the current AML risk stratification and provides guidance for precision medicine in AML.

Furthermore, combining ES@Cu(Ⅱ)-MOF with an anti-programmed cell death-ligand 1 (PD-L1) antibody converted the immunosuppressive tumor microenvironment to an immunogenic microenvironment, thus effectively inhibiting breast tumor growth. Overall, this work provides an innovative approach utilizing nanozymes to facilitate cuproptosis for cancer treatment, which potentially enhances the effectiveness of immune checkpoint inhibitor-based immunotherapy.

Foretinib and elesclomol were predicted to exert strong inhibitory effects on SW13 cells by inhibiting the expression of CDH2 and CDH13. These data indicate that CDH2 and CDH13 are promising targets for precise treatment of ACC and may serve as new biomarkers for ACC prognosis.

With Cu-DPPZ-Py+ and Cu-Elesclomol, there is strong evidence that the triggering cuproptosis significantly drives mitochondrial DNA (mtDNA) release to activate innate immunity via cyclic GMP-AMP synthase-stimulation of interferon genes (cGAS-STING), which can improve T cell antitumor immunity in vivo. By contrast, it is observed that Cu-DPPZ-Ph treated tumor cells could release intracellular caspase-3, resulting in apoptosis-associated immunosuppression. This study supports insights into how cuproptosis bridges cGAS-STING immune pathways, contributing to the development of cuproptosis-based antitumor immunotherapy.

P=N/A, N=1000, Not yet recruiting, Karolinska Institutet

The study developed an MSS CC cuproptosis model using 50 nM elesclomol and 1 μM CuCl2...Cuproptosis in MSS CC cells enhances the cytotoxicity of CD8+ T cells, which may be achieved through downregulation of the WNT signaling pathway and decreased expression of PD-L1. In the future, drugs that can induce cuproptosis may be a promising approach to improve MSS CC immunotherapy.

Elesclomol inhibits glioblastoma development via inducing cuproptosis, regulated by NFκB1/FDX1 axis.

Taken together, there is a great potential for HOXC6 to become a prognosis biomarker and contribute to develop treatment strategies for LUAD patients. Further mechanism exploration and drug development for HOXC6 are needed.

Cell experiments were conducted to verify whether FDX1 was involved in cuproptosis of Caki-1 cells induced by Elesclomol...This study provides compelling evidence that cuproptosis is closely linked to the prognosis of KIRC. FDX1 holds promise as a viable biomarker and therapeutic target for assessing the effectiveness of tumor immunotherapy in KIRC.

We developed a prognostic model constructed by 6 CRRMRs to assess overall survival and immune microenvironment of CRC patients. YTHDC2 might regulate cuproptosis in multiple ways.

Knockdown of TCF4 or pharmacological Wnt/β-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.

To trigger cuproptosis, copper-ionophore elesclomol (ES) had to be employed for the copper-transporting-mediated process...This enabled an increased infiltration of cytotoxic CD8+ T cells and consequently enhanced antitumor immune responses for successfully suppressing fibrosarcoma growth. Thus, the copper(II)-based metal-organic framework nano-regulator offered a promising approach for inducing cuproptosis and cuproptosis-stimulated ICD for cancer immunotherapy.

Finally, we validated the accuracy of FCRLs in hepatocellular carcinoma cell lines using induction agents (elesclomol and erastin). Cellular assays revealed significant changes in the expression of AC019080.5, AC145207.5, MIR210HG, and LINC01063 in HCC cell lines following the addition of ferroptosis and cuproptosis inducers. We created a signature of four FCRLs that accurately predicted survival in HCC patients, laid the foundation for basic research related to ferroptosis and cuproptosis in hepatocellular carcinoma, and provided therapeutic recommendations for HCC patients.

Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Cell viability assays showed that the glutathione and its precursor N-acetylcysteine could significantly rescue the cell death under either mono or combination treatment, demonstrating that GSH acts at the crossing point in the regulation network of cuproptosis and ferroptosis. Significantly, the reconstitution of xCT expression and knockdown of FDX1 cells have been found to contribute to the tolerance of mono treatment but have little recovery impact on the combined treatment. Collectively, these findings suggest that a synergistic interaction leading to the induction of multiple programmed cell death pathways could be a promising approach to enhance the effectiveness of therapy for MDS.

This study constructed a new cuproptosis-related gene signature that has a good prognostic capacity in assessing the outcome of OC patients. This study enhances our understanding of cuproptosis associated with ovarian cancer aggressiveness, cross-talk with immunocytes, and serves as a novel chemotherapy strategy.

ES-Cu can induce cuproptosis in AML cells, which provides a new idea for the treatment of AML.

In a comprehensive the drug susceptibility analysis, we found that patients with high expression of CDC45 had high sensitivity to various chemotherapeutic agents, among which 5-fluorouracil, docetaxel, cisplatin, and elesclomol were most evident. Enrichment analysis revealed that CDC45 and its associated genes may play crucial roles in muscle biofunction, whereas GSEA demonstrated significant enrichment of gene sets pertaining to G protein-coupled receptor ligand binding and G alpha (i) signaling events. Our study elucidates that upregulation of CDC45 is intricately associated with immune cell infiltration and holds promising potential as a favorable prognostic marker and a novel diagnostic biomarker for GC.

In our study, we demonstrated that elesclomol, as a carrier of copper ions, caused an upregulation of protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), which plays a role in regulating substrate selectivity of protein phosphatase 1 during cuproptosis. Mechanistically, we investigated that PPP1R15A activated translation initiation by dephosphorylating eukaryotic translation initiation factor 2 subunit alpha at the S51 residue through protein phosphatase 1 and phosphorylating eukaryotic translation initiation factor 4E binding protein 1 at the T70 residue. In addition, PPP1R15A reduced H3K4 methylation by altering the phosphorylation of histone methyltransferases, which led to the silencing of MYC and G2M phase arrest.

Finally, we show that ascorbate serves to enhance the oxidising effects of the MM therapeutic drug Elesclomol in both established MM cells in vitro and primary cell cultures ex vivo. Together, these results suggest that ascorbate selectively enhances DNA damage and cell-killing in MM cells. This raises the option of incorporating ascorbate into clinical oxidative therapies to treat MM.

Our study revealed the relationship between OXPHOS and tendency of cuproptosis in ESCC, and malignant cells with this characteristic exerted immunosuppressive signals and indicated poor prognosis. Furthermore, we constructed the constructed the regulatory network in high cuproptosis-OXPHOS ESCC and identified HMGA1 as a potential regulator molecule of cuproptosis mediated by elesclomol.

Herein, we develop a sodium alginate hydrogel consisting of elesclomol-Cu and galactose to induce persistent cuproptosis, leading to the reduction of PD-L1 for radio-immunotherapy of colon tumors...Consequently, the sensitization of tumor to radiotherapy and immunotherapy is significantly improved, further prolonging the survival of tumor-bearing mice in both local and metastatic tumors. Our study introduces an approach that combines cuproptosis with immunotherapy and radiotherapy.

Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.

Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.

Given the growing interest in the use of copper in the presence of the ionophore elesclomol (CuES) for the treatment of gliomas, we investigated the effect of this compound on the surround parenchyma-namely neurons and astrocytes in vitro...As neurons express high levels of metallothioneins basally, these results may partially account for their resistance to CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells which contrasts with the cell selectivity profile of zinc, another biologically relevant metal.

Our team's previous research found that ICC patients prone to cuproptosis possessed a more satisfactory long-term prognosis and a more sensitive response to copper carrier Elesclomol...We constructed precise diagnostic and treatment strategies for ICC patients prone to cuproptosis and further explored the intracellular and extracellular mechanisms of ICC cells prone to cuproptosis. Further work with large prospective cohorts will help verify these conclusions.

Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.

Induction of cuprotosis by elesclomol (ES) significantly repressed the in vitro and in vivo growth of thyroid cancer cells, simultaneously elevated Cu level and expression of FDX1, whereas depletion of FDX1 abolished these effects. Knockdown of FDX1 decreased the lipoylation level of DLAT and DLST in thyroid cancer cells, alleviated cuprotosis-induced cell death, simultaneously upregulated the levels of PA and α-KG. These findings demonstrated that FDX1 promotes the cuprotosis of thyroid cancer cells via regulating the lipoylation of DLAT.

Our research has identified a new prognostic biomarker and provides some innovative insights into the diagnosis and therapy of patients with COAD.

Elesclomol, a potent copper ionophore, significantly altered expressions of seven CRGs in CRCs, indicating their relationship with cuproptosis. The cuproptosis-related gene signature could serve as a potential prognostic predictor for colorectal cancer patients and may offer novel insights into clinical cancer therapeutics.

To the best of our knowledge, this is the first time that ES is radiolabeled with [Cu]CuCl to [Cu][Cu(ES)]. We demonstrated superior therapeutic effects of [Cu][Cu(ES)] compared to [Cu][Cu(ATSM)] and [Cu]CuCl and that [Cu][Cu(ES)]-PET is feasible. [Cu][Cu(ES)] is a promising theranostic agent for hypoxic solid tumors.

Cuproptosis and DLAT as a promising biomarker could help to determine the prognosis of HCC and may offer novel insights for effective treatment.

Our findings proposed that combination of ferroptosis inducers and copper ionophores to co-targeting ferroptosis and cuproptosis could be a novel therapeutic strategy for primary liver cancer.

Additionally, NP@ESCu was further combined with anti-programmed cell death protein ligand-1 antibody (?PD-L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with ?PD-L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.

In vitro experiments showed that a hub cuproptosis-related gene, TIGD1, could significantly regulate cuproptosis in CRC after exposure to elesclomol...Since a certain concentration of copper in CRC cells is important, cuproptosis may provide a new target for cancer therapy. This study may provide novel insights into the treatment of CRC.

The expressions of immunological checkpoints, ferroptosis-, m6A-, and m7G-related genes, type II interferon (INF) response, major histocompatibility complex (MHC class-I), and the IC50 of the copper-based carrier drug elesclomol were significantly different between the 2 groups of the CRs. Furthermore, the scRNA-seq analysis showed that most CRGs were mainly upregulated in endothelial cells. The novel CRs could predict the prognosis of GC.

Our study identified a new cuproptosis-related gene signature that could predict the prognosis of HCC patient. Besides, the upregulated PDXK could promote the proliferation and metastasis of HCC. And PDXK deficiency facilities cuproptosis in HCC. Therefore, these fundings highlighted that PDXK might serve as a potential diagnostic and therapeutic target for HCC.

Subsequently, we found 2-deoxy-D-glucose, a glucose metabolism inhibitor, sensitized cuproptosis. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.