Current anti-tumor strategies majorly rely on the targeted delivery of functional nanomedicines to tumor region, neglecting the importance of effective infiltration of these nanomedicines in whole tumor tissue. This process normally causes the quick endocytosis by the tumor cells at surface layer of tumor tissue, resulting in the restriction of the penetration of these nanomedicines and limited therapeutic region, which would not be able to treat the entire tumor tissue. Herein, we prepared a series of engineered gold nanoparticles (Au-MBP NPs) with step-wise charge reversal in different acid environments that could entirely infiltrate into the whole tumor tissue and then perform tumor-specific photothermal-chemodynamic-immunotherapy to achieve the complete and accurate tumor treatment. These Au-MBP NPs consisted of AuNPs, thiol modified piperidine (SH-PD, charge reversal group), thiol modified benzoyl thiourea (SH-BTU, copper chelator) and 11-mercaptoundecanoic acid (MUA) with different proportions. Once these Au-MBP NPs arrived tumor tissue, the decreasing pH values from shallow to deep region of tumor tissue separately induced the charge reversal of these nanoparticles from negative to positive, allowing them to bind with negatively charged tumor cells at designed area to occupy the whole tumor for further therapy. Following with the internalization by tumor cells, these Au-MBP NPs would selectively capture the excessive Cu2+ to decrease the available copper in tumor cells, resulting in the inhibition of tumor metastasis via the copper metabolism blockade. On one hand, the captured Cu2+ also induced the aggregation of Au-MBP NPs, which in situ generated the photothermal agents in tumor cells for tumor-specific photothermal therapy (PTT). On the other hand, the chelated Cu2+ ions were reduced to Cu+, which catalyzed the high concentration of intracellular H2O2 to produce cytotoxic hydroxyl radical (•OH), exerting tumor-specific chemodynamic therapy (CDT). Furthermore, the immune-associated tumor antigens were also generated during PTT and CDT processes via immunogenic cell death (ICD), which further matured the dendritic cells (DCs) and then activated CD4+ and CD8+ T cells to turn on the immunotherapy, resulting in additional anti-tumor and anti-metastasis effects. Both in vitro and in vivo results indicated that these Au-MBP NPs possessed enormous potential for effectively suppressing primary and metastatic tumors.

Metastasis is the primary cause of cancer associated deaths globally. Loss of function of Scribble, a cell polarity regulator and tumor suppressor gene, is associated with many forms of human cancers but its role in cell proliferation and metastasis remains unknown. We generated metastatic cancer condition in Drosophila using UASRNAi-GAL4 system by knockdown of Scribble in the wing imaginal discs and tracked metastasis events from early to late pupae (0hr-84 h s) using fluorescence microscopy. Here, we report, for the first time, that the knockdown of Scribble alone could lead to the development of primary tumor in the wing imaginal discs, which is capable of establishing metastasis, apparently leading to secondary tumor formation in pupae at early stage, eventually resulting in absolute pupal lethality without organ development. MMP1, a metastasis biomarker, levels were assessed during pre-and post-metastatic phases in pupae using qRT-PCR and Western blot analysis. Further, we analyzed the proteome of Scribble knockdown induced tumor-bearing pupae by 2-D gel electrophoresis followed by MALDI-TOF MS to identify some novel proteins possibly involved in the progression of tumorigenesis and metastasis events. Six differentially expressed proteins, Obp 99b, Fer2LCH,CG13492, Hsp23, Ubiquitin and Colt, were identified in Scrib knockdown pupae and validated their expression using qRT-PCR. Thus, our results suggested that loss of Scrib alone capable of causing metastasis, without the need for cooperative interaction with oncogenic Ras. The newly identified proteins could be important candidates for biomarker/therapeutic target against Scrib associated metastatic cancers.

Cancer remains the second leading cause of death worldwide, emphasizing the critical need for effective treatment and control strategies. Essential minerals such as copper, iron, zinc, selenium, phosphorous, calcium, and magnesium are integral to various biological processes and significantly influence cancer progression through altered metabolic pathways. For example, dysregulated copper levels promote tumor growth, while cancer cells exhibit an increased dependency on iron for signaling and redox reactions. Zinc influences tumor development through pathways such as Akt-p21. Selenium, primarily through its role in selenoproteins, exhibits anticancer potential but may also contribute to tumor progression. Similarly, dietary phosphate exacerbates tumorigenesis, metastasis, and angiogenesis through signaling pathway activation. Calcium, the most abundant mineral in the body, is tightly regulated within cells, and its dysregulation is a hallmark of various cancers. Magnesium deficiency, on the other hand, promotes cancer progression by fostering inflammation and free radical-induced DNA mutations. Interestingly, magnesium also plays a dual role, with low levels enhancing epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis. This complex interplay of essential minerals underscores their potential as therapeutic targets. Dysregulation of these minerals and their pathways could be exploited to selectively target cancer cells, offering novel therapeutic strategies. This review summarizes current research on the abnormal accumulation or depletion of these microelements in tumor biology, drawing evidence from animal models, cell lines, and clinical samples. We also highlight the potential of these minerals as biomarkers for cancer diagnosis and prognosis, as well as therapeutic approaches involving metal chelators, pharmacological agents, and nanotechnology. By highlighting the intricate roles of these minerals in cancer biology, we aim to inspire further research in this critical yet underexplored area of oncology.

Cuproptosis, a novel form of copper (Cu)-dependent programmed cell death, is induced by directly binding Cu species to lipoylated components of the tricarboxylic acid (TCA) cycle. Since its discovery in 2022, cuproptosis has been closely linked to the field of materials science, offering a biological basis and bright prospects for the use of Cu-based nanomaterials in various disease treatments. Owing to the unique physicochemical properties of nanomaterials, Cu delivery nanosystems can specifically increase Cu levels at disease sites, inducing cuproptosis to achieve disease treatment while minimizing the undesirable release of Cu in normal tissues. This innovative nanomaterial-mediated cuproptosis, termed as "nanocuproptosis", positions at the intersection of chemistry, materials science, pharmaceutical science, and clinical medicine. This review aims to comprehensively summarize and discuss recent advancements in cuproptosis across various diseases, with a particular focus on cancer. It delves into the biochemical basis of nanomaterial-mediated cuproptosis, the rational design for cuproptosis inducers, strategies for enhancing therapeutic specificity, and cuproptosis-centric synergistic cancer therapeutics. Beyond oncology, this review also explores the expanded applications of cuproptosis, such as antibacterial, wound healing, and bone tissue engineering, highlighting its great potential to open innovative therapeutic strategies. Furthermore, the clinical potential of cuproptosis is assessed from basic, preclinical to clinical research. Finally, this review addresses current challenges, proposes potential solutions, and discusses the future prospects of this burgeoning field, highlighting cuproptosis nanomedicine as a highly promising alternative to current clinical therapeutics.

Nuclear medicine has emerged as a critical modality in the diagnostic and therapeutic management of urological malignancies, particularly prostate cancer. Advances in single-photon emission computed tomography/computed tomography (CT) and positron emission tomography/CT (PET/CT) have enhanced tumor assessment across staging, treatment response, and recurrence settings. Molecular imaging, which offers insights beyond traditional anatomical imaging, is increasingly integral in specific clinical scenarios. Theranostic nuclear medicine, which combines diagnostic imaging with targeted therapy, has become a well-established treatment option, particularly for patients with metastatic castration-resistant prostate cancer (mCRPC). The development of the prostate-specific membrane antigen (PSMA) radioligands has revolutionized clinical management by enabling precise disease staging and delivering effective radioligand therapy (RLT). Ongoing research aims to refine the role of PSMA PET imaging in staging and treatment monitoring, while optimizing PSMA-targeted RLT for broader clinical use. Given that prostate cancer remains highly prevalent, the anticipated increase in the demand for RLT presents both challenges and opportunities for nuclear medicine services globally. Theranostic approaches exemplify personalized medicine by enabling the tailoring of treatments to individual tumor biology, thereby improving survival outcomes and maintaining patients' quality of life with minimal toxicity. Although the current focus is on advanced disease, future research holds promise for expanding these strategies to earlier stages, potentially enhancing curative prospects. This evolving field not only signifies a paradigm shift in the care of prostate cancer patients but also underscores the growing importance of nuclear medicine in delivering precision oncology.

This study outlines the sustainable synthesis of hybrid biopolymer hydrogels supported with octahedral Cu2O nanoparticles (NPs), alongside their biological assessments and characterizations. A composite hydrogel made of chitosan and guar gum (CS-GG) was employed as a template for the environmentally friendly synthesis of nanoparticles. Leveraging their electron-rich functional groups, the biopolymers acted as stabilizing agents for the Cu2O NPs and as green reductants, facilitating the reduction of copper ions. The material's physicochemical properties were thoroughly examined using advanced techniques, such as X-ray diffraction (XRD), Field-Emission Scanning Electron Microscopes (FE-SEM), Eneregy Dispersive X-ray Electron Spectroscopy (EDX), Fourier Transformed Infrared Spectroscopy (FT-IR), Transmission Electron Microscopy (TEM) and ICP-OES. The resulting CS-GG/Cu2O NPs nanocomposite was investigated as a reusable heterogeneous nanocatalyst, demonstrating its efficiency in the phosphine-free, palladium-free, and ligand-free synthesis of various stilbene derivatives with high yields through the Sonogashira coupling reaction. The catalyst showed no significant reduction in activity after being reused seven times consecutively. The cytotoxic effects of the CS-GG/Cu2O NPs nanocomposite on NCI-H661 lung cancer cells and normal cells (HUVEC) were assessed over 48 h using MTT assay. The cancer cell's viability decreased after exposure to the CS-GG/Cu2O NPs, with an IC50 value of 82 μg/mL. The CS-GG/Cu2O NPs nanocomposite controls the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) system, which in turn impacts apoptosis and cell proliferation in NCI-H661 cells, according to a detailed examination of the mTOR pathway. The pathway could act a role in the cell cycle inhibition and apoptosis induced by the CS-GG/Cu2O NPs nanocomposite. The CS-GG/Cu2O NPs nanocomposite could be a useful natural anti-cancer agent for the treatment of lung cancer.

Cu(II) ions play a critical role in tumor growth and metastasis, making in vivo high-resolution imaging of Cu(II) crucial for understanding its role in tumor pathophysiology. However, designing suitable molecular probes for this purpose remains challenging. Herein, we report the development of a photoacoustic probe for specific in vivo imaging of Cu(II) in tumors. This probe utilizes β-galactoside as a targeting group and incorporates a unique self-immobilization strategy. Upon β-galactosidase-mediated cleavage, the probe generates a reactive quinone methide intermediate that covalently binds to intracellular proteins, enabling selective tumor accumulation. The probe exhibits a ratiometric photoacoustic response to Cu(II) with high selectivity over that of other biological species. In vitro and in vivo studies demonstrated the efficacy of the probe for Cu(II) imaging in tumors. This research provides valuable insights into the role of Cu(II) in tumorigenesis and may facilitate the development of diagnostic and therapeutic approaches for cancer.

Copper ion (Cu2+) has been revealed to be involved in the occurrence and development of oral squamous cell carcinoma (OSCC), making copper-mediated chemodynamic therapy (Cu-CDT) a promising treatment strategy for OSCC by elevating Cu2+ levels to generating a large amount of reactive oxygen species (ROS). However, the excessive reduced glutathione (GSH) in the tumor microenvironment can scavenge the ROS generated by Cu-CDT. While the directional co-delivery of Cu2+ and GSH-depleting agents shows promise for Cu-CDT in OSCC therapy, their rapid metabolism and the superficial nature of OSCC lesions necessitate tailored drug formulations to ensure effective bioavailability. To counteract this challenge, this work proposed a practical hydrogel-supported ROS-GSH regulation strategy, which involves the on-demand design of a copper ion-crosslinked guanosine-based hydrogel (GCD) containing dimethyl fumarate (DMF, which conjugates with GSH for consumption). It can directionally and sustainably co-deliver Cu2+ and DMF to OSCC lesions under mildly acidic pH conditions, thereby enhancing Cu-CDT efficiency through improved Cu2+ utilization and DMF-driven GSH depletion. As anticipated, the strategy sustains the generation of hydroxyl radicals, effectively inducing apoptosis and suppressing cell proliferation in CAL-27 cells, which consequently inhibits the growth of OSCC tumors. Therefore, this work highlights the GCD hydrogel's great potential as a promising Cu-CDT therapeutic platform.

Copper (Cu) has long been a concern for human health. While previous studies have explored the toxic effects of Cu, no study is available on the relationship between the Cu redox state transformation and biotoxicity in higher organisms. In this study, we explored the gut and liver toxicity caused by the overflow of Cu(I) at low doses of Cu exposure. Here, we first elucidated the digestive and metabolic systems as the main toxic target sites by a systematic epidemiological analysis. Then, ICP-MS analysis verified that the gut and liver were the top two Cu-high-accumulated organs in zebrafish exposed to 10 and 100 μg/L waterborne Cu for 72 h. In-situ Cu(I) and Cu(II) imaging techniques demonstrated that exogenous Cu(II) was converted to Cu(I) in the zebrafish gut. Furthermore, transcriptomic sequencing revealed that the high overflow of Cu(I) induced gut toxicity by cell cycle arrest in the G phase. However, the substantial accumulation of Cu(I) disrupted the metabolism of energy source nutrients and energy supply, leading to hepatic toxicity. This study provides new insights into the toxic mechanism based on Cu redox state and emphasizes the health risks associated with Cu exposure in the digestive and metabolic systems.

Copper is a trace element which is essential for biological organisms, and its homeostatic balance is important for living organisms to maintain the normal function. When the copper homeostasis is disordered, the cellular function and structure will be disrupted. Excess copper cause oxidative stress and DNA damage in cells, thereby inducing regulated cell death such as apoptosis and necroptosis. Excess copper in mitochondria can bind to lipoylated proteins in the tricarboxylic acid (TCA) cycle and cause them to aggregate, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cancer cells have a greater demand for copper compared to normal tissue, and high levels of copper ions are closely associated with tumour proliferation and metastasis. The anti-tumor mechanisms of copper include the production of oxidative stress, inhibition of the ubiquitin-proteasome system, suppression of angiogenesis, and induction of copper-dependent cell death. Targeting copper is one of the current directions in oncology research, including the use of copper ion carriers to increase intracellular copper levels to induce oxidative stress and cuproptosis, as well as the use of copper ion chelators to reduce copper bioavailability. However, copper complexes have certain toxicity, so their biosafety needs to be improved. Emerging nanotechnology is expected to solve this problem by utilizing copper-based nanomaterials (Cu-based NMs) to deliver copper ions and a variety of drugs with different functions, thereby improving the anti-tumor efficacy and reducing the side effects. Therefore, a thorough understanding of copper metabolic processes and the mechanism of cuproptosis will greatly benefit anti-tumor therapy. This review summarizes the processes of copper metabolism and the mechanism of cuproptosis. In addition, we discuss the current anti-tumor paradigms related to copper, we also discuss current nanotherapeutic approaches to copper mortality and provide prospective insights into the future copper-mediated cancer therapy.

Chemodynamic therapy (CDT), which utilizes transition metal ions to catalyze Fenton-like reactions for the eradication of tumor cells, has attracted substantial attention in the field of nanocatalysis. However, the therapeutic efficacy of CDT as a monotherapy is often limited by an insufficient level of hydrogen peroxide (H2O2) and the overexpressed glutathione (GSH) within tumor cells. Because of the high copper content in tumor tissues, a copper ionophore was strategically employed to enhance the intracellular accumulation of copper, thereby potentiating the CDT effect. Additionally, bovine serum albumin (BSA) was used to modify the copper ionophore, naphthazarin (Nap), to promote its targeting efficacy for tumor cells and to ensure its biosafety. The BSA-coated Nap nanoparticles, which could recruit Cu2+ in situ, were further deposited onto the surface of a manganese carbonate nanocube (Nap-BM NPs). The synergistic action of copper and manganese ions accelerated the decomposition of H2O2 into hydroxyl radicals (•OH) and consumed intracellular GSH, leading to cellular mortality via mitochondrial pathways. With low cytotoxicity and good biocompatibility in normal cells, the developed Nap-BM NPs significantly enhanced therapeutic outcomes by leveraging multiple Fenton-like reaction mechanisms to augment CDT, offering promising potential for clinical applications and contributing valuable insights into the field.

Disulfidptosis is an emerging type of programmed cell death related to ROS accumulation and aberrant disulfide bond formation. Multiple myeloma (MM) is the second most prevalent hematologic malignancy characterized by a high synthesis rate of disulfide bond-rich proteins and chronic oxidative stress. However, the relationship between disulfidptosis and MM is still unclear.

Using the non-negative matrix factorization and lasso algorithm, we constructed the disulfidptosis-associated subtypes and the prognostic model on the GEO dataset. We further explored genetic mutation mapping, protein-protein interactions, functional enrichment, drug sensitivity, drug prediction, and immune infiltration analysis among subtypes and risk subgroups. To improve the clinical benefits, we combined risk scores and clinical metrics to build a nomogram. Finally, in vitro experiments examined the expression patterns of disulfidptosis-related genes (DRGs) in MM.

By cluster analysis, we obtained three subtypes with C2 having a worse prognosis than C3. Consistently, C2 exhibited significantly lower sensitivity to doxorubicin and lenalidomide, as well as a higher propensity for T-cell depletion and a non-responsive state to immunotherapy. Similarly, in the subsequent prognostic model, the high-scoring group had a worse prognosis and a higher probability of T-cell dysfunction, immunotherapy resistance, and cancer cell self-renewal. DRGs and risk genes were widely mutated in cancers. Subtypes and risk subgroups differed in ROS metabolism and the p53 signaling pathway. We further identified eight genes differentially expressed in risk subgroups as drug targets against MM. Then 27 drugs targeting the high-risk group were predicted. Based on the DRGs and risk genes, we constructed the miRNA and TF regulatory networks. The nomogram of combined ISS, age, and risk score showed good predictive performance. qRT-PCR of cell lines and clinical specimens provided further support for prognostic modeling.

Our research reveals the prognostic value of disulfidptosis in MM and provides new perspectives for identifying heterogeneity and therapeutic targets.

The mechanism of how toxicant exposure leads to aggressive tumors remains unresolved. A genetic-based hypothesis predicts that under stress, the transcription of growth-related genes will be inhibited by the activation of mitogenic pathways, redirecting energy toward stress response and increasing survival. This hypothesis fails to explain why epidemiological data suggest that growth and stress response are activated, as patients exposed to toxicants exhibit more aggressive growth than nonexposed individuals. This co-occurrence requires increased energy availability to prevent the activation of mitogenic pathways, as seen in the Warburg effect. We hypothesize that if pollutant effects cease, it might drive aggressive cancer, as excess energy that is no longer used for stress response can fuel rapid growth. We model this allocation between growth and stress response as a trophic competition using the Lotka-Volterra equations and using as input RNA-Seq data from growth- and stress-related genes obtained from cancer cells exposed to copper, cadmium, and carboplatin. Our findings suggest that the energy allocation to growth and its rate of allocation is higher in exposed than nonexposed tumors and results in overgrowth in unexposed cells. This study helps to understand how certain scenarios, such as partial or total cessation of exposure, in toxicant-related cancer can drive cancer aggressiveness.

Cuproptosis, a recently identified form of copper-dependent cell death, arises from intracellular copper dyshomeostasis. As an essential trace element, copper plays a critical role in bioenergetic metabolism, redox regulation, and synaptic transmission. However, excessive copper exerts cytotoxic effects through multiple pathways, including increased reactive oxygen species (ROS) production, apoptotic cascade activation, necrotic membrane rupture, inflammatory responses, and mitochondrial dysfunction. Distinct from other cell death mechanisms, cuproptosis is characterized by copper ion binding to acetylated mitochondrial respiratory chain proteins, leading to pathogenic protein aggregation, iron-sulfur cluster depletion, and cellular collapse. Emerging evidence underscores aberrant copper accumulation and resultant proteotoxic stress as pivotal contributors to the pathogenesis of multiple musculoskeletal pathologies, including osteoporosis, osteoarthritis, sarcopenia, osteosarcoma, intervertebral disc degeneration, spinal cord injury, and biofilm-associated orthopedic infections. Understanding the spatiotemporal regulation of cuproptosis may provide novel opportunities for advancing diagnostic and therapeutic approaches in orthopedic medicine. This review synthesizes current insights into the molecular mechanisms of cuproptosis, its pathogenic role in musculoskeletal diseases, and the potential for biomarker-driven therapeutic interventions.

Bilirubin, a metabolite of hemoglobin, was long thought to be a harmful waste product, but recent studies have found it to have antioxidant and anti-tumor effects. With the extensive research on the mechanism of malignant tumor development, the antioxidant effect of bilirubin is increasingly becoming a hotspot in anti-cancer research. At present, there are two main views on the relationship between bilirubin and cancer, namely, its pro-cancer and anti-cancer effects, and in recent years, studies on the relationship between bilirubin and cancer have not been systematically summarized, which is not conducive to the further investigation of the role of bilirubin on cancer. To understand the multifaceted role of bilirubin in tumorigenesis as well as to develop more effective and affordable antitumor therapies, this review provides an overview of the effects of bilirubin on tumors in terms of oxidative, inflammatory, and cellular signaling pathways, as well as the resulting therapeutic ideas and approaches.

Thyroid cancer (THCA) is the most prevalent endocrine tumor, and its incidence continues to increase every year. However, the processes underlying the aggressive progression of thyroid cancer are unknown. We concentrated on the prognostic and biological importance of thyroid cancer cuproptosis-related genes in this investigation. Genomic and clinical data were obtained from the UCSC XENA website, and cuproptosis-related genes were obtained from the FerrDb website. We performed differential expression analysis and Cox regression analysis to identify possible predictive targets associated with thyroid cancer prognosis. To assess the role of CDKN2A in thyroid cancer and the ability to predict prognosis on the basis of the CDKN2A expression level, we performed immunohistochemical staining, survival analysis, immunological analysis, functional analysis, and clinical analysis with respect to CDKN2A gene expression. CDKN2A expression levels were found to be inversely correlated with thyroid cancer prognosis. Higher levels of CDKN2A expression were associated with higher T, N, and clinicopathological stage and more residual tumor cells. Through univariate and multivariate Cox regression analyses, the CDKN2A expression level was shown to be linked with thyroid cancer patients' overall survival (OS). Moreover, we discovered that CDKN2A expression was linked to a dysfunctional tumor immune microenvironment. The study shows that CDKN2A, a cuproptosis-related gene, can be used as a prognostic marker for thyroid cancer.

Cuproptosis, along with RNA methylation regulators, has recently come to the fore as innovative mechanisms governing cell death, exerting profound impact on the onset and progression of multiple cancers. Nonetheless, the prognostic implications and underlying regulatory mechanisms of them associated with prostate cancer (PCa) remain to be thoroughly investigated.

Genomic and clinical data for PCa from The Cancer Genome Atlas datasets were analyzed to identify a prognostic model through univariate and Least Absolute Shrinkage and Selection Operator Cox regression analyses that were validated utilizing external datasets. We used receiver operating characteristic curves and C-index to evaluate the accuracy of our prognostic model. In conjunction with this, we conducted single-cell RNA sequencing (scRNA-seq) analyses to investigate underlying mechanisms and evaluate the degree of immune infiltration, as well as to assess patients' responses to diverse chemotherapy agents. Especially, qPCR assay was utilized to unveil the expression of signature genes in PCa.

We meticulously selected six Cuproptosis-Associated RNA Methylation Regulators (CARMRs) to establish a risk prognosis model, which was further verified to obtain enhanced predictive capacity in external validation cohorts. Insights from immune infiltration and scRNA-seq analyses have elucidated the immune characteristics of PCa, and highlighted the immunosuppressive role of regulatory T cells on immune response. Additionally, drug susceptibility analysis demonstrated that patients with PCa in the low-risk category derived better benefit from bicalutamide treatment, whereas those in the high-risk group exhibited a favor response to adriamycin and docetaxel treatments. The qPCR and immunohistochemistry (IHC) staining assays also reveal the a dramatically altered expression pattern of TRDMT1 and ALYREF in PCa tissues.

In general, we established a model involving CARMRs that can better predict the risk of recurrence of PCa and have identified the possible mechanisms affecting PCa progression, thereby promoting further research in this field.

A water-soluble and biologically benign glucose-appended quinoline-benzothiazole conjugate (L) has been synthesized and characterized using various spectroscopy techniques. The recognition properties of L show selective recognition of Cu+ ions among other biological metal ions including Cu2+ ions in PBS buffer at pH 7.4. L exhibited a switch-on fluorescence enhancement upon the addition of Cu+ with a detection limit of 1.48 × 10-8 M in an aqueous medium. Job's plot confirmed the 1 : 1 binding ratio observed between probe L and Cu+ ions with an association constant (Ka) of 1.46 × 105 M-1. The proposed complex binding mechanism was supported by UV-Vis, fluorescence and ESI-MS. The coordination features of the {L + Cu+} complex were delineated using DFT computational calculations. Furthermore, L was successfully applied for intracellular fluorescence bio-imaging of Cu+ ions in L929 living cells, suggesting that it holds significant potential for Cu+ ion bio-imaging and disease diagnosis.

Cyclin-dependent kinase 1 (CDK1) is the pivotal kinase responsible for initiating cell division. Its activation is dependent on binding to regulatory cyclins, such as CCNB1. Our research demonstrates that copper binding to both CDK1 and CCNB1 is essential for activating CDK1 in cells. Mutations in the copper-binding amino acids of either CDK1 or CCNB1 do not disrupt their interaction but are unable to activate CDK1. We also reveal that CCNB1 facilitates the transfer of copper from ATOX1 to CDK1, consequently activating its kinase function. Disruption of copper transfer through the ATOX1-CCNB1-CDK1 pathway can impede CDK1 activation and halt cell cycle progression. In summary, our findings elucidate a mechanism through which copper promotes CDK1 activation and the G2/M transition in the cell cycle. These results could provide insight into the acquisition of proliferative properties associated with increased copper levels in cancer and offer targets for cancer therapy.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs, mostly affecting young and middle-aged women. Significant questions remain as to its pathogenesis, especially the triggers for the associated interstitial lung disease (SSc-ILD). We examined the extent to which SSc and SSc-ILD were related to oxidative stress and altered metal homeostasis at the air-lung interface.

In this case-control study, we recruited 20 SSc patients, of which 11 had SSc-ILD. Eighteen healthy individuals were recruited as age-matched healthy controls, for a total of 38 study participants. Low molecular weight antioxidants (ascorbate, urate and glutathione), metal transport and chelation proteins (transferrin and ferritin) and metals (Fe and Cu) concentrations, including a measure of the catalytically active metal pool, were determined in respiratory tract lining fluid (RTLF) collected by bronchoalveolar lavage from the SSc group and compared with healthy controls.

In the SSc group, 14 individuals were of female sex (70%) and the median age was 57 years (range 35-75). We observed evidence of oxidative stress in the RTLFs of SSc patients, characterised by increased concentrations of glutathione disulphide (GSSG, P<0.01), dehydroascorbate (DHA, P<0.05) and urate (P<0.01). This was associated with elevated RTLF Fe (P=0.07) and Cu (P<0.001), and evidence of a catalytic metal pool, demonstrated by an enhanced rate of ascorbate oxidation in the recovered lavage fluid (p<0.01). Cu concentrations were significantly associated with the ascorbate depletion rate (r=0.76, P<0.001), and GSSG (r=0.38, P<0.05) and protein carbonyl (r=0.44, P<0.01) concentrations. Whilst these markers were all increased in SSc patients, we found no evidence for an association with SSc-ILD.

These data confirm the presence of oxidative stress in the airways of SSc patients and, for the first time, suggest that an underlying defect in metal homeostasis at the air-lung interface may play a role in disease progression.

In this paper, the isopropyl ester derivatives LOiPr and L2OiPr of bis(pyrazol-1-yl)acetic acid and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid were used as chelators for the preparation of new Cu(i) phosphane complexes 1-4. They were synthesized by the reaction of [Cu(CH3CN)4]PF6 and triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane with LOiPr and L2OiPr ligands, in acetonitrile or acetonitrile/methanol solution. The authenticity of the compounds was confirmed by CHN analysis, 1H-, 13C- and 31P-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). Furthermore, the electronic and molecular structures of the selected Cu(i) coordination compound 3 were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), and the local structure around the copper ion site was studied combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modelling. Triphenylphosphine as a coligand confers to [Cu(LOiPr)(PPh3)]PF6 (1) and [Cu(L2OiPr)(PPh3)]PF6 (3) a significant antitumor activity in 3D spheroidal models of human colon cancer cells. Investigations focused on the mechanism of action evidenced protein disulfide-isomerase (PDI) as an innovative molecular target for this class of phosphane copper(i) complexes. By hampering PDI activity, copper(i) complexes were able to cause an imbalance in cancer cell redox homeostasis thus leading to cancer cell death - a non-apoptotic programmed cell death.

Copper has emerged as a promising target for cancer therapy, with extensive studies on copper accumulation-induced cuproptosis. However, the potential of copper depletion-induced cuproptosis remains largely unexplored. Recently, Zhou et al. (M. Zhou, F. Muhammad, Y. Zhang, T. Li, J. Feng, J. Zhao and H. Wei, Chem. Sci., 2025, https://doi.org/10.1039/D4SC04712E) reported an innovative strategy for copper depletion-based cuproptosis. Notably, this approach leverages the solubility product principle, a mechanism not previously addressed in studies, to achieve effective tumor therapy through the disruption of copper homeostasis.

Imaging abnormal copper/iron with effective fluorescent tools is essential to comprehensively put insight into many pathological events. However, conventional coordination-based detection is mired in the fluorescence quenching induced by paramagnetic Cu(II)/Fe(III). Moreover, the strong chelating property of the probe will consume dissociative metal ions and inevitably interfere with the physiological microenvironment. Here, a new strategy is developed by employing this aberrant Cu(II)/Fe(III) to catalyze bond cleavage for fluorescent imaging of them. A short series of near-infrared fluorescent molecules (NIRB1-NIRB6) is devised as substrates, wherein the specific C═C bonds can be effectively cleaved to activate red fluorophore by Cu(II)/Fe(III) catalyzing. Representatively, NIRB1 is applied for fluorescent imaging of Cu(II)/Fe(III) in living cells, zebrafish, and Alzheimer's disease (AD)-afflicted mouse brains which is of significance to monitor metal safety. The successful cleavage of C═C bonds catalyzed by Cu(II)/Fe(III) enriches the application of abiotic bond cleavage reactions in metal detection, and may also inspire the development of fluorescent tools for the future diagnosis and therapy of diseases.

The development of Cu(II) ionophores for targeted disruption of aberrant redox homeostasis in cancer cells has been considered an appealing strategy in the field of anticancer research. This study presents the first identification of tanshinone I (Ts1), a natural o-quinone, as a Cu(II) ionophore. Structure-activity relationship studies on tanshinones and mechanistic investigations reveal that the presence of Cu(II) effectively promotes the tautomerization of Ts1 from its diketo to keto-enol forms, thereby facilitating its sequential proton-loss Cu(II) chelation, and enabling it to function as a Cu(II) ionophore due to its structural features including the presence of an o-quinone moiety, a benzyl hydrogen, and a large conjugated system. The unique property allows Ts1 to preferentially induce copper accumulation in human hepatoma HepG2 cells over human umbilical vein endothelial cells, by releasing copper driven by reduced glutathione (GSH). This copper accumulation leads to a reduction in the GSH-to-oxidized glutathione ratio and the generation of reactive oxygen species, ultimately triggering apoptosis of HepG2 cells. The findings not only provide support for o-quinones as innovative types of anticancer Cu(II) ionophores, but also shed light on the previously unrecognized role of Ts1 as a potent Cu(II) ionophore for eradicating cancer cells by selectively disrupting their redox regulation programs, resembling a "Trojan horse".

Electronic cigarettes (e-cigarettes) have emerged as a potential alternative to traditional smoking and may aid in tobacco harm reduction and smoking cessation. E-cigarette use has notably increased, especially among young non-tobacco users, raising concerns due to the unknown long-term health effects. The oral cavity is the first and one of the most crucial anatomical sites for the deposition of e-cigarette aerosols. E-cigarette aerosols contain nicotine, flavors, volatile organic compounds, heavy metals, carcinogens, and other hazardous substances. These aerosols impact the oral cavity, disrupting host-microbial interactions and triggering gingivitis and systemic diseases. Furthermore, oral inflammation and periodontitis can be caused by proinflammatory cytokines induced by e-cigarette aerosols. The toxic components of e-cigarette aerosols increase the cellular reactive oxygen species (ROS) levels, reduce antioxidant capacity, increase DNA damage, and disrupt repair processes, which may further contribute to harmful effects on oral epithelum, leading to inflammatory and pre-malignant oral epithelial lesions. In this review, we analyze the toxicological properties of compounds in e-cigarette aerosols, exploring their cytotoxic, genotoxic, and inflammatory effects on oral health and delving into the underlying molecular mechanisms. Further research is essential to understand the impact of e-cigarettes on oral health and make informed regulatory decisions based on reliable scientific evidence.

Copper is an essential trace element, yet chronic copper exposure can lead to toxicity in humans, and high levels of copper have been found in the blood or tumors of patients with various forms of cancer and may affect cancer severity and response to treatment. Copper is required for the activation of cytochrome c oxidase (CcO), the mitochondrial complex that facilitates oxidative phosphorylation (OXPHOS)-mediated ATP production. We recently reported that the increased activation of CcO underlies the acquisition of treatment resistance in glioblastoma (GBM) cells. However, the potential role of copper in GBM progression or treatment resistance has not been investigated. Here, we present evidence that exposure to 20 µM copper, the maximum allowable limit for public water supplies set by the U.S. Environmental Protection Agency, promotes GBM tumor growth and reduces overall survival in vivo and increases GBM cell resistance to radiation and chemotherapy in vitro. In vitro exposure to 20 µM copper substantially increased the activity of CcO, elevated the rate and level of ATP production, and triggered a metabolic shift to an OXPHOS phenotype in GBM cells. Furthermore, copper exposure led to a substantial increase in the accumulation of glutathione and glutathione precursors in these cells. These findings establish copper as a tumor promoter in GBM and suggest that copper mediates these effects through the upregulation of CcO activity, which enhances OXPHOS metabolism and glutathione production.

Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short in selectivity. In this study, our objective was to improve the selectivity of glycoconjugates by replacing the oxygen atom with nitrogen by substituting the 8-HQ moiety with 8-aminoquinoline (8-AQ). The 8-AQ derivatives were functionalized through the amino group and linked to sugar derivatives (D-glucose or D-galactose) that were modified with an azide, alkylazide, or propargyl group at the anomeric position by copper(I)-catalyzed 1,3-dipolar azido-alkyne cycloaddition (CuAAC). The resulting glycoconjugates, as well as their potential metabolites, were evaluated for their ability to inhibit the proliferation of cancer cell lines (including HCT 116 and MCF-7) and a healthy cell line (NHDF-Neo). Two of the synthesized glycoconjugates (17 and 18) demonstrated higher cytotoxicity than their oxygen-containing counterparts and showed improved selectivity for cancer cells, thus enhancing their anticancer potential. Furthermore, it was found that glycoconjugates exhibited greater cytotoxicity in comparison to their potential metabolites.

Aging is intricately linked to various diseases including cancers, neurodegenerative disorders, and metabolic irregularities. Copper (Cu) overexposure has been found to be linked to many diseases during aging, particularly neurodegenerative diseases. Meanwhile, as an essential element, Cu has been implicated in key processes associated with aging, raising questions about its role in age-related health issues. This study delves into the mechanisms behind the copper imbalance during aging. By analyzing blood copper concentrations of healthy individuals (including data from healthy subjects (26 ≤ age ≤ 90, n = 62) and publicly available data from the National Health and Nutrition Examination Survey (18 ≤ age < 80, n = 1624)) and employing C57BL/6N male mice models (n = 22), we reveal a consistent age-related increase in copper levels, particularly in plasma. Utilizing stable copper isotopic analysis, copper-associated protein analysis, and metabolomic analysis, we trace the sources of Cu imbalance associated with aging. Our findings reveal that aged mice had a higher copper concentrations and an enrichment of light copper isotope (63Cu) in plasma compared to controls. Additionally, copper reductases and copper transporters are upregulated in the intestine tract, associated with the AMPK and mTOR signaling pathways. We suggest that aged mice have an abnormally high copper intake requirement, probably due to deregulated nutrient sensing, leading to increased expression levels of copper reductases and copper transporters for extra copper absorption in the intestines. This research provides a copper-centric perspective on the connection between deregulated nutrient sensing and aging, thus shedding light on the aspect of aging and copper overexposure.

Several copper-ligands, including 1,10-phenanthroline (Phen), have been investigated for anticancer purposes based on their capacity to bind excess copper (Cu) in cancer tissues and form redox active complexes able to catalyse the formation of reactive oxygen species (ROS), ultimately leading to oxidative stress and cell death. Glutathione (GSH) is a critical compound as it is highly concentrated intracellularly and can reduce and dissociate copper(II) from the ligand forming poorly redox-active copper(I)-thiolate clusters. Here we report that Cu-Phen2 speciation evolves in physiologically relevant GSH concentrations. Experimental and computational experiments suggest that at pH 7.4 mostly copper(I)-GSH clusters are formed, but a minor species of copper(I) bound to one Phen and forming ternary complexes with GSH (GS-Cu-Phen) is the redox active species, oxidizing quite efficiently GSH to GSSG and forming HO⋅ radicals. This minor active species becomes more populated at lower pH, such as typical lysosomal pH 5, resulting in faster GSH oxidation and HO⋅ production. Consistently, cell culture studies showed lower toxicity of Cu-Phen2 upon inhibition of lysosomal acidification. Overall, this study underscores that sub-cellular localisation can considerably influence the speciation of Cu-based drugs and that minor species can be the most redox- and biologically-active.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown etiology. Cuproptosis, a novel form of cell death, is characterized by cytotoxicity originating from copper ions. To date, the relationship between cuproptosis-related gene gliostatin (GLS) and RA.

All raw data were retrieved from the Gene Expression Omnibus (GEO) public database. The expression level of genes between RA and healthy samples was evaluated to identify differentially expressed genes. Then, LASSO regression was used to screen disease signature genes, and a nomogram was constructed based on five hub genes to predict disease scores. Validation experiments were performed using quantitative real-time PCR (qRT-PCR) to detect the most significant CRGs. Finally, the causal relationship between GLS and RA was analyzed through Mendelian randomization methodology.

Five differentially expressed CRGs (NLRP3, ATP7A, MTF1, GLS, and DBT) were identified between normal and RA samples, all of which were validated as disease-specific genes through LASSO regression analysis. Meanwhile, the nomogram demonstrated a positive correlation between RA and the expression of GLS. Furthermore, q-PCR revealed that the expression level of GLS was higher in RA patients compared to those in the control group. Taken together, a causal relationship between GLS and RA was corroborated through Mendelian randomization.

GLS, a cuproptosis-related gene, is closely associated with RA and plays a significant role in its diagnosis. Key Points • The causal relationship between GLS and RA is proved by Mendelian randomization.

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.

Atherosclerosis is a slow and complex disease that involves various factors, including lipid metabolism disorders, oxygen-free radical production, inflammatory cell infiltration, platelet adhesion and aggregation, and local thrombosis. Trace elements play a crucial role in human health. Many trace elements, especially metallic ones, not only maintain the normal functions of organs but also participate in basic metabolic processes. The latest studies have revealed a close correlation between trace elements and the occurrence and progression of atherosclerosis. The imbalance of these trace elements can induce atherosclerosis or accelerate its progression through various mechanisms, which poses a significant threat to human health. Therefore, exploring the specific mechanism of trace elements on atherosclerosis is highly significant. In this review, we summarized the roles and mechanisms of iron, copper, zinc, magnesium, and selenium homeostasis and imbalance in atherosclerosis development, in order to identify novel targets and therapeutic strategies for treating atherosclerosis.

Cuproptosis is a regulated form of cell death induced by the accumulation of metal ions and is closely linked to aspects of cellular drug resistance, cellular metabolism, and signalling pathways. Due to its crucial role in regulating physiological and pathological processes, cuproptosis has gained increasing significance as a potential target for anticancer drug development. In this review, we introduce the definition of cuproptosis and provide a comprehensive discussion of the mechanisms of cuproptosis. In addition, the methods for the detection of cuproptosis are summarized, and recent advances in cuproptosis in cancer therapy are reviewed, mainly in terms of elesclomol (ES)-mediated cuproptosis and disulfiram (DSF)-mediated cuproptosis, which provided practical value for applications. Finally, the current challenges and future development of cuproptosis-mediated cancer therapy are discussed. In summary, this review highlights recent progress on cuproptosis in cancer therapy, offering novel ideas and strategies for future research and applications.

Copper(II) complexes are very promising candidates for platinum-based anticancer agents. Herein, three Cu (II) complexes (1-3) containing 1,8-naphthalimide ligands were synthesized and characterized by FT-IR, elemental analysis, ESI-MS and single crystal X-ray diffraction (complex 3). In addition, a control compound (complex 4) without 1,8-naphthalimide ligand was synthesized and characterized. The in vitro anticancer activity of the synthesized complexes against five cancer cell lines and one normal cell line was evaluated by MTS assay. The results displayed the antitumor activity of complexes 1-3 was controlled by the aliphatic chain length of ligands, their cytotoxicity was in the order 3 > 2 > 1, giving the IC50 values ranging from 2.874 ± 0.155 μM to 31.47 ± 0.29 μM against five cancer cell lines. Complex 4 showed less activity in comparison with complex 1-3. Notably, complexes 1-3 displayed much higher selectivity (SI = 2.65 to 10.16) compared to complex 4 (SI = 1.0), indicated that the introduction of 1,8-naphthalimide group not only increased the activity of this series of compounds but also enhanced their specific selectivity to cancer cells. Compound 3 induced apoptosis in cancer cells and blocked the S-phase and G2/M of cancer cells. The interaction with DNA of complexes 3 and 4 was studied by UV/Vis spectroscopic titrations, competitive DNA-binding experiment, viscometry and CD spectra. The results showed that complex 3 interacted with DNA in an intercalating mode, but the interaction mode of compound 4 with DNA was electrostatic interaction.

The proteasomal system is becoming a target for the treatment of several diseases, especially in cancer therapy. The present study aims to develop a novel copper complex that inhibits the proteasome in skin squamous cell carcinoma. New molecules based on the copper complex were synthesized for the first time to assess their potential as proteasome inhibitors, specifically targeting squamous cell carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in mouse models. Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), and energy dispersive X-ray analysis (EDX) were carried out to characterize this new copper complex. Notably, the presence of a papilloma (skin tumor) was confirmed by histopathological analysis. Subsequent investigation included the quantification of proteasome levels using a sandwich ELISA test, and the catalytic activity of the 20S proteasome was determined by measuring the fluorescence emitted after the cleavage of 7-amino-4-methylcoumarin (AMC). Hence, X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration and biological activity of copper Schiff base complex, which exhibits high proteasome inhibitory activities with particular selectivity of β5 subunit. The pharmacokinetic properties (ADMET) of the copper complex named Cu(L1) showed encouraging results with very low toxicity, distribution, and absorption. Structure-activity relationship (SAR) information obtained from Cu(L1) demonstrated its selectivity and potent inhibition for β5 subunit. In this regard, this copper complex has emerged as a novel therapy for skin cancer.

The human microbiome is the complex ecosystem consisting of trillions of microorganisms that play a key role in developing the immune system and nutrient metabolism. Alterations in the gut microbiome have been linked to cancer initiation, progression, metastasis, and response to treatment. Accumulating evidence suggests that levels of vitamins and minerals influence the gut environment and may have implications for cancer risk and progression. Bifidobacterium has been reported to reduce the colorectal cancer risk by binding to free iron. Additionally, zinc ions have been shown to activate the immune cells and enhance the effectiveness of immunotherapy. Higher selenium levels have been associated with a reduced risk of several cancers, including colorectal cancer. In contrast, enhanced copper uptake has been implicated in promoting cancer progression, including colon cancer. The interaction between cancer and gut bacteria, as well as dysbiosis impact has been studied in animal models. The interplay between prebiotics, probiotics, synbiotics, postbiotics and gut bacteria in cancer offers the diverse physiological benefits. We also explored the particular probiotic formulations like VSL#3, Prohep, Lactobacillus rhamnosus GG (LGG), etc., for their ability to modulate immune responses and reduce tumor burden in preclinical models. Targeting the gut microbiome through antibiotics, bacteriophage, microbiome transplantation-based therapies will offer a new perspective in cancer research. Hence, to understand this interplay, we outline the importance of micronutrients with an emphasis on the immunomodulatory function of the microbiome and highlight the microbiome's potential as a target for precision medicine in cancer treatment.

Cancer and cardiovascular disease (CVD) are leading causes of mortality and thus represent major health challenges worldwide. Clinical data suggest that cancer patients have an increased likelihood of developing cardiovascular disease, while epidemiologic studies have shown that patients with cardiovascular disease are also more likely to develop cancer. These observations underscore the increasing importance of studies exploring the mechanisms underlying the interaction between the two diseases. We review their common physiological processes and potential pathophysiological links. We explore the effects of chronic inflammation, oxidative stress, and disorders of fatty acid metabolism in CVD and cancer, and also provide insights into how cancer and its treatments affect heart health, as well as present recent advances in reverse cardio-oncology using a new classification approach.

Contamination and toxicity of copper (Cu) in soils are global issues, particularly in regions where Cu-based fungicides are utilized. Elevated Cu concentrations can lead to soil contamination and pose significant risks to the ecosystem, including plant life, wildlife, and human health. The application of biochar has been proposed as a viable strategy to mitigate Cu accumulation in plants. However, there is no quantitative and data-based consensus on the impact of biochar on plant Cu accumulation. In this meta-analysis, 624 data records from 65 published literature were collected and the effects of various factors, including biochar properties, experimental conditions, and soil properties on Cu accumulation in plants, were examined through meta-subgroup analysis and meta-regression models. The results obtained indicate a significant dose-dependent effect of biochar in decreasing Cu concentration in plants by an average of 23.45%. Soils with acidic pH values and medium textures were more conducive for biochar to mitigate Cu accumulation in plant tissues. In addition, manure biochar and green waste biochar were found to be more successful in decreasing Cu concentrations in plants compared to other biochar types. Biochar types with pyrolysis temperatures of > 600 °C and pH values of ≥ 10 resulted in greater decreases in plant Cu concentration. Regarding biochar application, biochar minimum range of 1% in potting experiments and 20 t/ha in field experiments have been recommended to effectively decrease Cu concentration in plants. Overall, these findings provide valuable insights into Cu transfer mitigation through food chain to human bodies and for policymakers to take preventive measures.

Copper (Cu) is a vital micronutrient necessary for proper development and function of mammalian cells and tissues. Cu mediates the function of redox active enzymes that facilitate metabolic processes and signaling pathways. Cu levels are tightly regulated by a network of Cu-binding transporters, chaperones, and small molecule ligands. Extensive research has focused on the mammalian Cu homeostasis (cuprostasis) network and pathologies, which result from mutations and perturbations. There are roles for Cu-binding proteins as transcription factors (Cu-TFs) and regulators that mediate metal homeostasis through the activation or repression of genes associated with Cu handling. Emerging evidence suggests that Cu and some Cu-TFs may be involved in the regulation of targets related to development-expanding the biological roles of Cu-binding proteins. Cu and Cu-TFs are implicated in embryonic and tissue-specific development alongside the mediation of the cellular response to oxidative stress and hypoxia. Cu-TFs are also involved in the regulation of targets implicated in neurological disorders, providing new biomarkers and therapeutic targets for diseases such as Parkinson's disease, prion disease, and Friedreich's ataxia. This review provides a critical analysis of the current understanding of the role of Cu and cuproproteins in transcriptional regulation.

Copper is a vital trace element in oxidized and reduced forms. It plays crucial roles in numerous biological events such as redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy, and immune modulation. Maintaining the balance of copper in the body is essential because its deficiency and excess can be harmful. Abnormal copper metabolism has a two-fold impact on the development of tumors and cancer treatment. Cuproptosis is a form of cell death that occurs when there is excessive copper in the body, leading to proteotoxic stress and the activation of a specific pathway in the mitochondria. Research has been conducted on the advantageous role of copper ionophores and chelators in cancer management. This review presents recent progress in understanding copper metabolism, cuproptosis, and the molecular mechanisms involved in using copper for targeted therapy in cervical cancer. Integrating trace metals and minerals into nanoparticulate systems is a promising approach for controlling invasive tumors. Therefore, we have also included a concise overview of copper nanoformulations targeting cervical cancer cells. This review offers comprehensive insights into the correlation between cuproptosis-related genes and immune infiltration, as well as the prognosis of cervical cancer. These findings can be valuable for developing advanced clinical tools to enhance the detection and treatment of cervical cancer.