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.

Overall, our predictive signature displayed potential value in the prediction of overall survival of HCC patients and might provide valuable clues for personalized therapies.

We also identified that certain anticancer drugs, such as bortezomib, elesclomol, GW843682X, and nilotinib, showed significant sensitivity in the high FARS score group. RGS2 may thus be studied further as a new target for immunotherapy in future studies on gastric cancer. In summary, the FARS model developed here enhances our understanding of lipid metabolism in the TME in gastric cancer, and provides a theoretical basis for predicting tumor prognosis and clinical treatment.

Immune response and drug sensitivity analysis revealed that immunotherapy or elesclomol may have a favorable treatment effect in the high FDX1 expression group and sunitinib or axitinib may work better in the low FDX1 expression group. In conclusion, we constructed a CRGs prognostic model and revealed that FDX1 could serve as a prognostic biomarker and predict therapeutic response in ccRCC. The study will provide a novel, precise, and individual treatment strategy for ccRCC patients.

Moreover, chemotherapy drugs or inhibitors, such as axitinib, cisplatin, doxorubicin, and elesclomol, may be considered as potential therapeutic drugs for patients in high-risk groups. Finally, inhibition of AL512306.3 and ZEB1-AS1 significantly suppressed the cell proliferation in colon cancer cells. These results provide novel insights into the pathogenesis of colon cancer and offer promising biomarkers with the potential to guide research on carcinogenesis and cancer treatment.

Anisomycin also significantly inhibited the proliferation of OCSCs in vitro, and its effect was similar to that of elesclomol and buthionine sulfoximine (BSO), suggesting that it has the potential to promote cuproptosis of OCSCs...Therefore, our molecular biology experiments combined with bioinformatics analysis results suggest that the direct target of anisomycin-induced cuproptosis in ovarian cancer stem cells is probably a YY1 transcription factor. By inhibiting the expression and activity of YY1, anisomycin could not activate the transcriptional activity of the core genes of the lipoic acid pathway (i.e.,FDX1, DLD, DLAT, and PDHB), and induced the accumulation of cytotoxic substances, eventually leading to potential cuproptosis in ovarian cancer stem cells.

Furthermore, patients in the high-risk group are more sensitive to targeted therapy or chemotherapy, including bosutinib, elesclomol, lenalidomide, midostaurin, pazopanib and sunitinib, while the low-risk group is more likely to benefit from immunotherapy. Finally, in vitro study confirmed the oncogenic significance of ATG14 in both HCT116 and SW480 cells, whose overexpression increased CRC cell proliferation, colony formation, and migration. In conclusion, we developed a novel mitophagy-related gene signature that can be utilized not only as an independent predictive biomarker but also as a tool for tailoring personalizing treatment for CRC patients, and we confirmed ATG14 as a novel oncogene in CRC.

The status of TP53 somatic mutation was also closely related to the risk score. In this study, we established a new prediction signature of eight genes related to cuproptosis and the TCA process, which can effectively predict the prognosis of HCC patients.

Additionally, the hub cuproptosis-associated gene (CAG) FDX1 presented a dysregulated expression pattern in human ccRCC samples, and it was confirmed to effectively promote the killing effects of copper ionophore elesclomol as a direct target. In vitro functional assays revealed the prominent anti-cancer role of FDX1 in ccRCC. Cuproptosis played an indispensable role in the regulation of TME features, tumor progression, and long-term prognosis of ccRCC.

An experiment in vitro showed FDX1 is downregulated by elesclomol, resulting in inhibiting cell viability of bladder cancer, clear cell renal cell carcinoma, and prostate cancer cells. Our study reveals that FDX1 can serve as a potential therapeutic target and prognostic marker for various malignancies due to its vital role in tumorigenesis and tumor immunity.

The novel 4-MTRG signature is a promising biomarker in predicting clinical outcomes for colon cancer patients, and TIMP1, a member of the signature, may be a sensitive regulator of the progression of colon cancer.

However, the high-CUS group showed higher sensitivity to sunitinib, axitinib, and elesclomol. We developed a targeted therapy and immunotherapy strategy for advanced KIRC based on CUS. Our findings provide new insights into the relationship among cuproptosis, metabolism, and immunity in KIRC.

Furthermore, addition of binimetinib, a MEK inhibitor, to elesclomol increased its synthetic lethality to GNAQ/11-mutant UM cells, thereby overriding drug resistance. These studies reveal a novel mechanistic basis for repurposing elesclomol by showing that copper homeostasis is a GNAQ/11-specific vulnerability in UM. Elesclomol may provide a new therapeutic path for selectively targeting malignant GNAQ/11-mutant UM.

Our study characterized three stemness-related subtypes with distinct prognosis and TME patterns in CRC patients, and a 5-gene stemness-risk model was constructed by comprehensive bioinformatic analyses. We suggest our stemness model has prospective clinical implications for prognosis evaluation and might facilitate physicians selecting prospective responders for preferential use of current immune checkpoint inhibitors.

We discovered that AZD7762, Sunitinib, Cytarabine, Docetaxel, Vinblastine, and Elesclomol exhibited lower IC50 in the low-score group. Six iron metabolism and ferroptosis-related genes were associated with the prognosis, CNV, TMB, and immune cell infiltration of ESCC. Some potential anti-cancer drugs and compounds may be helpful for OS.

Thermal stimulation can promote EMT in A549 and NCI-H446 cells and promote cell migration and invasion in vitro and in vivo by upregulation of Hsp70. This process is associated with the promotion of SUMO modification of HIF-1α.

Gene ontology analysis was used to screen signal pathways related to HSPA1A-, HSPA1B-, HSPA7-, and HSPA9- high phenotype. In summary, the increased expressions of HSPA1A1, HSPA1B, and HSPA7 were associated with poor prognosis, while that of HSPA9 was related to favorable prognosis for colon cancer patients.

We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.