Copper (Cu) is an important metal pollutant commonly found in aquatic environment. Cu-based nanoparticles (NPs) have been increasingly fabricated, and led to cytotoxicity in aquatic animals. Herein, the mechanisms underlying the CuSO4/Cu-NPs-mediated perturbation of the hepatopancreatic mitochondrial function at different concentrations were investigated and compared. After exposing Eriocheir sinensis to 0 (control), 5, 50, and 500 μg/L CuSO4 and 10 μg/L Cu-NPs for 21 days, hepatopancreases were retrieved. The results revealed that Cu-NPs or excess CuSO4 induced ultrastructural damage following a time-dose effect, as indicated by swelling and degeneration of the lumen of hepatic tubules. Cu-NPs or excess CuSO4 exposure decreased the antioxidative capacity and led to the over-accumulation of reactive oxygen species (ROS). Moreover, the mitochondrial membrane potential (MMP) was reduced and apoptosis induced. Additionally, both CuSO4 and Cu-NPs increased the numbers of mitophagosomes and the mRNA and protein levels of microtubule associated protein 1 light chain 3 beta (LC3B), and triggered mitophagy through BCL2 interacting protein 3 like (BNIP3L)/Beclin1 pathway. Altogether, this study provides a basis for exploring Cu-mediated potential mitochondrial autophagy activation mechanisms, uncovered the difference between CuSO4 and Cu-NPs.

Cuproposis is a new-found mechanism of cell death, and the role of cuproposis-related genes (CRGs) in pancreatic cancer prognosis remains uncertain.

DECRGs were identified from TCGA and GTEx databases. Five OS-associated hub genes were screened using Cox regression and LASSO analyses. A prognostic model was constructed and validated by survival analysis. GSEA, gene mutation, small-molecule drugs, immune-infiltrating and TF/miRNA/mRNA network were investigated to determine the underlying mechanism of 5-CRGs. In addition, RT-qPCR, and WB were applied to validate the expression of 5-CRGs. CCK8, colony formation and transwell assays were used to prove the function of LIPT1 in PC.

PDP1, DLAT, DBT, LIAS, and LIPT1 were screened as hub genes. 5-CRGs prognostic model established the low-risk population has a longer OS. There was a high the risk score value for the prediction in clinicopathological features. The forest plots showed that age, N stage and the RiskScore were the significant independent risk indicators. T cells CD4 memory resting and Mast cells are the amplest immune cell subpopulations in the high-score individuals. The expression of 5 CRGs exhibited significant differences in PC cell lines and tissues, LIPT1-knockdowning inhibited proliferation and invasion of pancreatic cancer cell lines.

Five CRGs relevant to pancreatic cancer prognosis were identified. Meanwhile, a new and accurate five CRGs prognostic model of pancreatic cancer was constructed. In addition, LIPT1 may promote proliferation, invasion and migration of pancreatic cancer cell lines. This may have a specific guiding value for future development of precise anti-cancer treatment strategies.

Cuproptosis represents a novel mechanism of cellular demise characterized by the intracellular buildup of copper ions. Unlike other cell death mechanisms, its distinct process has drawn considerable interest for its promising applications in managing inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence indicates that copper metabolism and cuproptosis may exert dual regulatory effects within pathological cellular environments, specifically modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. An appropriate level of copper may promote disease progression and exert synergistic effects, but exceeding a certain threshold, copper can inhibit disease development by inducing cuproptosis in pathological cells. This makes abnormal copper levels a potential new therapeutic target for IBD and CRC. This review emphasizes the dual function of copper metabolism and cuproptosis in the progression of IBD and CRC, while also exploring the potential application of copper-based therapies in disease treatment. The analysis further delineates the modulatory influence of tumor immune microenvironment on cuproptosis dynamics, while establishing the therapeutic potential of cuproptosis-targeted strategies in circumventing resistance to both conventional chemotherapeutic agents and emerging immunotherapies. This provides new research directions for the development of future cuproptosis inducers. Finally, this article discusses the latest advances in potential molecular targets of cuproptosis and their related genes in the treatment of IBD and CRC, highlighting future research priorities and unresolved issues.

Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.

Immune checkpoint blockade (ICB) therapy is an emerging strategy for renal cell carcinoma (RCC). However, its clinical efficacy remains constrained by its inherently poor immunogenicity and insufficient cytotoxic T lymphocyte (CTL) infiltration. Herein, we engineer a biomimetic copper nanozyme (Cu2O-OMV) by integrating Cu2O nanoparticles with bacterial outer-membrane vesicles (OMVs) to activate the antitumor immune response and synergize with ICB therapy. The Cu2O-OMV nanozyme exhibits peroxidase (POD)-like catalytic activity and releases Cu+ to exert Fenton-like activity, generating cytotoxic hydroxyl radicals (·OH) for tumor inhibition. Furthermore, Cu+ accumulation promotes the occurrence of cuproptosis, leading to the mitochondrial aggregation of lipoylated dihydrolipoamide S-acetyltransferase and depletion of ferredoxin 1. Notably, Cu2O-OMV concurrently activates pyroptosis via the noncanonical inflammasome pathway through its intrinsic lipopolysaccharide cargo, directly inhibiting tumor growth and inducing inflammatory cytokine release. The coordinated induction of cuproptosis and pyroptosis synergistically amplifies immunogenic cell death to enhance tumor immunogenicity, thereby promoting dendritic cell maturation and CTL infiltration. After combining with αPD-L1, it effectively destroys tumor cells to activate the antitumor immune response, thereby inhibiting tumor metastasis. Our study demonstrates a biomimetic nanozyme-driven strategy that harnesses dual cuproptosis-pyroptosis pathways to enhance the tumor immunogenicity and amplify the ICB efficacy, offering a transformative approach for RCC immunotherapy.

Excessive copper becomes toxic, driving inflammation, and, when copper exceeds a certain threshold, it even leads to a novel programmed cell death termed cuproptosis. However, disordered copper metabolism and its mechanism in pulpitis remain unclear. In this work, we found that lipoteichoic acid (LTA) or lipopolysaccharides (LPS) triggered copper deposition in pulpitis and consequently intensified cuproptosis by impeding the pentose phosphate pathway (PPP). We initially assessed the copper content in pulpitis tissues via inductively coupled plasma mass spectrometry and observed significantly greater concentrations than in healthy pulp tissues. We found that a relatively high copper content was triggered by LTA or LPS, leading cells to cuproptosis. Stimulation of LTA or LPS induced copper deposition and cuproptosis, worsening the progression of pulpitis in vivo. Mechanistically, we found that copper detoxification is dependent on the PPP. We used a 13C-glucose stable isotope-tracing experiment to assess the effect of glucose utilization on cuproptosis. Excessive copper hindered the PPP, resulting in an inadequate generation of nicotinamide adenine dinucleotide phosphate to replenish glutathione and counteract copper toxicity. The PPP regulates the phenotype, function, and survival of preodontoblast-like cells in cuproptosis. Our findings revealed the intricate interplay among bacteria, copper homeostasis, and metabolic reprogramming, providing potential strategies for host-targeted therapy in pulpitis.

Glioblastoma (GBM) is a disease with high morbidity and poor prognosis. The combination of traditional Chinese and Western medicine and cuproptosis are known to serve important roles in the treatment of GBM. However, targeting cuproptosis to treat GBM by combining traditional Chinese and Western medicine has not been extensively investigated. Therefore, the present study focused on the diagnosis and treatment of GBM based on cuproptosis. Through a bioinformatics approach, a cuproptosis‑related prognostic model was first constructed. Next, this prognostic model was found to be closely related to immune infiltration, DNA mutation and DNA methylation through multi‑omics analysis. The present study indicated the cell clusters in GBM tissues and the risk scores in each cluster based on single‑cell sequencing data derived from Gene Expression Omnibus. Notably, by screening the CellMiner database, EMD‑1204831 was found to exhibit a high correlation with the risk score. Next, through network pharmacology and molecular docking analysis, the risk score‑related gene collagen type XXII α1 chain (COL22A1) was identified as the target of kaempferol, which is the active component of Ginseng. Notably, kaempferol could decrease the proliferation of GBM cells by inhibiting COL22A1 expression in cell experiments. Finally, kaempferol and EMD‑1204831 had an obvious inhibitory effect on the growth of GBM and sensitized GBM to cuproptosis inducers via COL22A1 in cell and animal experiments. Overall, the present study revealed a cuproptosis‑related combined regimen for GBM.

Metal accumulation in marine invertebrates has attracted significant attention owing to its toxicity to human health. Although T. sazae is a major edible fish resource in Japan, metal accumulation in the soft body of T. sazae has not been examined. In this study, the metal concentrations, chemical forms, and distributions in soft tissues of T. sazae were characterized. We observed the extensive iron accumulation i.e. over 10,000 μg/g dw in the digestive gland of T. sazae. The iron accumulator in the digestive gland was ferritin, an iron storage protein. Analysis of elemental distribution revealed that ferritin in the digestive gland contains phosphorus, and that μm-sized brown granular cells were responsible for iron storage, with over 70,000 μg/g ww of iron accumulated at the most concentrated point. T. sazae probably contributes to the ocean's iron cycle by grazing on iron-rich algae and rocks and storing iron using unique ferritin.

Intracellular copper levels should be maintained within a controlled range to obtain copper homeostasis. Cuproptosis, a newly discovered form of cell death, occurs when excessive copper ions bind to the lipoylated enzymes in the tricarboxylic acid cycle, which leads to lipoylated protein aggregation, proteotoxic stress, and ultimately cell death. Herein, we summarize the current knowledge regarding copper metabolism, the discovery and molecular mechanism of cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various liver diseases, including hepatocellular carcinoma (HCC), Wilson disease (WD), metabolic-associated fatty liver disease (MAFLD), liver fibrosis, hepatic ischemia-reperfusion injury (HIRI) and drug-induced liver injury (DILI). Understanding the mechanism of cuproptosis can not only provide deeper insights into the pathogenesis of liver diseases but also open up new avenues for the development of targeted therapies.

Hepatocellular carcinoma (HCC) is the main phenotype of liver cancer with a poor prognosis. Copper is vital in liver function, and HCC cells rely on it for growth and metastasis, leading to cuproplasia. Excessive copper can induce cell death, termed cuproptosis. Tumor microenvironment (TME) is pivotal in HCC, especially in immunotherapy, and copper is closely related to the TME pathogenesis. However, how these two mechanisms contribute to the TME is intriguing.

We conducted the latest progress literature on cuproplasia and cuproptosis in HCC, and summarized their specific roles in TME and treatment strategies. The mechanisms of cuproplasia and cuproptosis and their relationship and role in TME have been deeply summarized. Cuproplasia fosters TME formation, angiogenesis, and metastasis, whereas cuproptosis may alleviate mitochondrial dysfunction and hypoxic conditions in the TME. Inhibiting cuproplasia and enhancing cuproptosis in HCC are essential for achieving therapeutic efficacy in HCC.

An in-depth analysis of cuproplasia and cuproptosis mechanisms within the TME of HCC unveils their opposing nature and their impact on copper regulation. Grasping the equilibrium between these two factors is crucial for a deeper understanding of HCC mechanisms to shed light on novel directions in treating HCC.

Pancreatic cancer (PC) has high lethality due to multiple reasons, and its limited response to conventional chemotherapy like gemcitabine (GEM) is a non-negligible one. Therefore, our study introduces Chlorophyllin (CHL) as an effective therapeutic candidate to enhance the therapeutic efficacy of GEM. Our results demonstrate that the combination of CHL and GEM exhibits a significant synergistic anti-tumor effect by targeting multiple oncogenic processes in PC, including inhibiting cell proliferation, invasion, and migration, as well as inducing cell apoptosis. Further investigations of mechanism have revealed that CHL induces cuproptosis in PC cells through a multifaceted process, involving depleting cellular intracellular glutathione (GSH), increasing reactive oxygen species (ROS) levels, and subsequently upregulating the HSP70 protein in response to heightened oxidative stress. Additionally, CHL releases free Cu2+, binds to the Ferredoxin 1 (FDX1) protein, and ultimately leads to the oligomerization of Dihydrolipoamide S-Acetyltransferase (DLAT) proteins to amplify the copper toxicity within PC cells. Moreover, in vivo experiments have demonstrated that the combination of CHL and GEM effectively inhibits the growth of subcutaneously transplanted tumors while maintaining a favorable biosafety profile. In conclusion, our study identifies CHL as a potent enhancer of GEM's anti-tumor effects in PC through the induction of cuproptosis, thus providing a novel therapeutic avenue for patients with PC.

Systemic sclerosis, also termed scleroderma, is a severe and debilitating autoimmune disease characterized by fibrosis, an aberrant immune response, and vascular dysfunction. Cell death is essential to the body's continued normal development as it removes old or damaged cells. This process is governed by several mechanisms, including programmed cell death through apoptosis, necrosis, and pyroptosis, as well as metabolic processes, such as ferroptosis and cuproptosis. This review describes the signaling pathways associated with each form of cell death, examining the linkages between these pathways, and discussing how the dysregulation of cell death processes is involved in the development of autoimmune disorders such as systemic sclerosis. Existing and promising therapeutic strategies aimed at restoring the balance of cell death in systemic sclerosis and other autoimmune disorders are also emphasized.

Protein post-translational modifications (PTMs) refer to covalent and enzymatic alterations to folded or nascent proteins during or after protein biosynthesis to alter the properties and functions of proteins. PTMs are modified in a variety of types and affect almost all aspects of cell biology. PTMs have been reported to be involved in cancer progression by influencing multiple signaling pathways. The mechanism of action of histone PTMs in cancer has been extensively studied. Notably, evidence is mounting that PTMs of non-histone proteins also play a vital role in cancer progression. In this review, we provide a systematic description of main non-histone PTMs associated with cancer progression, including acetylation, lactylation, methylation, ubiquitination, phosphorylation, and SUMOylation, based on recent studies.

Human respiratory syncytial virus (HRSV) infection is linked to significant morbidity and mortality in infants and young children worldwide, yet no effective treatment is available. Interferon α (IFNα), a major subtype among the IFN family, has demonstrated antiviral effects by activating the human immune system. Aerosol inhalation is a way of IFN administration that can enhance efficacy while decreasing serum IFNα concentrations and systemic exposure, thereby minimizing the risk of systemic toxicity. However, at present, human interferon α1b (IFNα1b) injection solution is used off-label for inhalation, raising safety concerns for infants. Additionally, natural IFNα1b contains a free sulfhydryl group from cysteine residue, increasing the risk of structural instability. Human serum albumin (HSA), an excipient in IFNα1b formulations, may pose safety risks to infants. To address these concerns, we developed GB05-human IFNα1b inhalation solution with optimized molecular design, expression system and formulation. First, GB05 protein was expressed in the periplasmic space to achieve easier purification. GB05 was engineered with a C86S mutation to prevent the formation of intermolecular disulfide bonds. Furthermore, GB05 was formulated according to regulations for inhalation solution, with a minimal HSA of 0.1 %, to ensure safety while preserving biological activity and stability. Plasma concentrations of GB05 following nebulization in cynomolgus macaques were significantly lower than those in the lungs, suggesting a reduced risk of systemic adverse events. Finally, GB05 showed good efficacy against HRSV infection in vitro and in vivo. In summary, GB05 is the first reported IFN inhalation solution manufactured in compliance with regulatory standards, to our knowledge, exhibiting safety and efficacy due to effectively local delivery. GB05 will fill the gap in the treatment of HRSV infection.

Liver ischemia-reperfusion injury (LIRI) is a critical challenge in liver transplantation, resection, and trauma surgeries, leading to significant hepatic damage due to oxidative stress, inflammation, and mitochondrial dysfunction. This review explores the cellular and molecular mechanisms underlying LIRI, focusing on ATP depletion, mitochondrial dysfunction, and the involvement of reactive oxygen species (ROS). Inflammatory pathways, including the activation of nuclear factor-kappa B (NF-κB) and the NLRP3 inflammasome, as well as pro-inflammatory cytokines such as TNF-α and IL-1β, play a crucial role in exacerbating tissue damage. Various types of cell death, including necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis and cuproptosis are also discussed. Therapeutic interventions targeting these mechanisms, such as antioxidants, anti-inflammatories, mitochondrial protectors, and signaling modulators, have shown promise in pre-clinical studies. However, translating these findings into clinical practice faces challenges due to the limitations of animal models and the complexity of human responses. Emerging therapies, such as RNA-based treatments, genetic editing, and stem cell therapies, offer potential breakthroughs in LIRI management. This review highlights the need for further research and the development of innovative therapeutic approaches to improve clinical outcomes.

High copper levels pose a risk to environmental and human health due to their toxicity and widespread industrial application, in which abnormal copper levels are associated with various diseases both in neurodegenerative diseases and plant growth. Thus, a turn-on fluorescent probe BBYD-Cu, based on donor-acceptor type structure, was designed and synthesized with easy preparations. BBYD-Cu can specifically recognized Cu2+ by 2-picolinic ester group, then released the fluorophore to enhance the fluorescent signals. With a detection limit of 31 nM, it displays extremely sensitive and precise Cu2+ detection. In addition, BBYD-Cu has the advantages of fast response speed (within 3 min), excellent selectivity and strong anti-interference ability for Cu2+. Significantly, the BBYD-Cu demonstrates superior detection and imaging performance even in intricate real-world environmental samples, biological nerve cells and plant soybean sprout root tissue.

Cancer is one of the most important challenges worldwide with an increasing incidence. However, most of patients with malignant cancer receiving traditional therapies have tumor recurrence and short-term 5-year survival. Herein, a novel Cu2O-MnO@PEG (CMP) nanomaterial is developed to treat tumors. CMP directly mediates cuproptosis in tumor cells. Meanwhile, CMP potentiates anti-tumor immune responses in the tumor microenvironment (TME) to induce tumor regression. CMP improves the tumor antigen processing and presentation of dendritic cells and tumor-associated macrophages, and further promotes CD8+ T cell responses, especially for cytotoxic CD8+ T cells and transitory exhausted CD8+ T cells. Additionally, CMP downregulates the proportion of Treg cells and CTLA-4 expression on Treg cells. Notably, CMP induces systemic immune responses against distant tumors and long-term immune memory. Furthermore, CMP synergized with PD-L1 mAb promotes tumor inhibition and sustains the anti-tumor efficacy post PD-L1 mAb treatment. Collectively, this strategy has the clinically therapeutic potential for tumors by facilitating cuproptosis in tumor cells and anti-tumor immune responses.

Pregnancy complications pose challenges for both pregnant women and obstetricians globally, with the pathogenesis of many remaining poorly understood. Recently coined as a mode of cell death, cuproptosis has been proposed but remains largely unexplored. This process involves copper overload, resulting in the accumulation of fatty acylated proteins and subsequent loss of iron-sulfur cluster proteins. This cascade induces proteotoxic stress, leading to cell death. In recent years, studies have indicated a connection between abnormal copper metabolism and several pregnancy-related diseases, including maternal placental dysplasia, gestational diabetes mellitus (GDM), gestational hypertension (PIH), preterm birth or abortion, as well as conditions in offspring such as intrauterine growth restriction (IUGR), allergic disease, Menkes disease, and Wilson's disease. Investigating the mechanism of cuproptosis and abnormal copper metabolism in these pregnancy-related diseases emerges as a critical research area. This article provides a concise review of cuproptosis mechanisms and emphasizes the association between abnormal copper metabolism and pregnancy-related diseases. Nevertheless, the doubtful viewpoints were also discussed.

Skin cutaneous melanoma (SKCM) is one of the most lethal cancers translating into 75% of skin cancer-related deaths. Despite the advances in SKCM management and treatment strategies, the overall survival of patients remains unsatisfactory due to the metastatic properties of SKCM as well as the absence of effective prognostic biomarkers. Recent studies have shown that overload copper renders accumulation of mitochondrial proteins and fuels a form of cell death at odds with known death mechanisms and is hinged on mitochondrial respiration, the so-called cuproptosis. However, the exact role of cuproptosis in SKCM development and progression is unknown, and painting a clear picture of its functions in SKCM is fraught with challenges. A more systematic investigation is justified. In this study, we were posed to dissect the clout and latent regulatory mechanisms of cuproptosis-related genes (CRGs) in reining in SKCM progression. Also, we identified three CRGs that stood out were used to construct a prognostic model, which could be employed to predict the prognosis of patients with SKCM. Finally, through pan-cancer analysis, we found that the four cuproptosis key genes play a role in multiple tumors, suggesting that cuproptosis may impact tumor progression at the pan-cancer level. Taken together, these findings may not only contribute to the development of treatment strategies but also provide clues for treatment decision-making.

Cuproptosis exhibits enormous application prospects in treatment. However, cuproptosis-based therapy is impeded by the limited intracellular copper ions, the nonspecific delivery, uncontrollable release, and chelation of endogenous overproduced glutathione (GSH). In this work, an ultrasound-triggered nanosonosensitizer (p-TiO2-Cu(I)) was constructed for Cu(I) delivery, on-demand release, GSH consumption, and deeper tissue response. When the nanomedicine was internalized into the tumor cells, ultrasound (US) induced the nanosonosensitizer to produce reactive oxygen species (ROS) to achieve sonodynamic therapy (SDT). GSH, acting as a hole trapping agent, improved the efficiency of SDT. Meanwhile, the downgrade of GSH was beneficial to cuproptosis and oxidative damage-based SDT in return. What is more, the US could regulate the release behavior of Cu(I). Cu(I) bonded to mitochondrial proteins and then aggregated the lipoylated protein, bringing about the turbulence of the tricarboxylic acid cycle. The combination of SDT and cuproptosis showed high matching to induce efficient cuproptosis and may inspire other cuproptosis-based nanosonosensitizer designs.

Highly responsive and optically selective (E)-1-((4-phenoxyphenyl) diazenyl)naphthalen-2-ol) sensor PDN with aggregation induced emission enhancement (AIEE) properties has been developed for the sequential detection of Cu2+ and L- Cysteine through fluorescence On-Off-On strategy. The selectivity of sensor depends on the presence of a diazo functional group and its appropriate cavity location in sensor molecule. Azo dye-based (E)-1-((4-phenoxyphenyl) diazenyl)naphthalen-2-ol) sensor PDN has been synthesized by utilizing a simple diazotization synthetic methodology that showed extraordinary AIEE behavior with bathochromic shift owing to the formation of J-aggregates. The morphology and size of aggregates were analyzed by SEM and DLS analysis, respectively. The calculated LOD of sensor PDN for Cu2+, and L-cysteine is 0.113 nM, and 84 nM, respectively. Fluorescence, UV-visible, LC-MS, 1H and 13C NMR titration were carried out to understand the interaction of sensor with Cu2+. The sensor was practically utilized in the sequential sensing of Cu2+ and Cys in real samples. Interestingly, sensor PDN was successfully employed for the sensing of a strong acid and base as well as the detection of Cu2+ ions in the solid state. Moreover, these experimental results were supported through DFT calculations.

Staphylococcus aureus (S. aureus) is a Gram-positive bacterium of significant clinical importance, known for its versatility and ability to cause a wide array of infections, such as osteoarticular, pulmonary, cardiovascular, device-related, and hospital-acquired infections. This review describes the most recent evidence of the pathogenic potential of S. aureus, which is commonly part of the human microbiota but can lead to severe infections. The prevalence of pathogenic S. aureus in hospital and community settings contributes to substantial morbidity and mortality, particularly in individuals with compromised immune systems. The immunopathogenesis of S. aureus infections involves intricate interactions with the host immune and non-immune cells, characterized by various virulence factors that facilitate adherence, invasion, and evasion of the host's defenses. This review highlights the complexity of S. aureus infections, ranging from mild to life-threatening conditions, and underscores the growing public health concern posed by multidrug-resistant strains, including methicillin-resistant S. aureus (MRSA). This article aims to provide an updated perspective on S. aureus-related infections, highlighting the main diseases linked to this pathogen, how the different cell types, virulence factors, and signaling molecules are involved in the immunopathogenesis, and the future perspectives to overcome the current challenges to treat the affected individuals.

This research investigated active biomolecules from the endophytic fungus Aspergillus unguis (CBMAI 2140), isolated from Passiflora incarnata leaves, as potential antibacterial agents against Xanthomonas citri subsp. citri, the causative agent of citrus canker. The fungal extract was obtained via liquid-liquid extraction with ethyl acetate. Antibacterial activity was assessed using the Resazurin Microtiter Assay Plate, determining inhibitory concentrations (IC90) and the minimum bactericidal concentration (MBC). The extract displayed microbicidal activity at 1050 µg ml-¹ and inhibited bacterial growth at 350 µg ml-¹. Fractionation of the extract via normal-phase column chromatography yielded six fractions, with fraction F11 showing the highest antibacterial potential (MBC: 200 µg ml-¹). Nuclear magnetic resonance analysis identified Unguinol as the main compound in F11. Fluorescence microscopy demonstrated rapid permeabilization of the X. citri cell membrane upon exposure to the compound, with significant effects observed after 15-30 min. Although no notable anti-biofilm activity was detected, this study represents the first report of Unguinol's antibacterial activity against Xanthomonas species. These findings highlight its potential for agricultural applications, contributing to sustainable development goal 2.

Acute kidney injury (AKI) is one of the most common and severe clinical renal syndromes with high morbidity and mortality. Ferroptosis is a form of programmed cell death (PCD), is characterized by iron overload, reactive oxygen species accumulation, and lipid peroxidation. As ferroptosis has been increasingly studied in recent years, it is closely associated with the pathophysiological process of AKI and provides a target for the treatment of AKI. This review offers a comprehensive overview of the regulatory mechanisms of ferroptosis, summarizes its role in various AKI models, and explores its interaction with other forms of cell death, it also presents research on ferroptosis in AKI progression to other diseases. Additionally, the review highlights methods for detecting and assessing AKI through the lens of ferroptosis and describes potential inhibitors of ferroptosis for AKI treatment. Finally, the review presents a perspective on the future of clinical AKI treatment, aiming to stimulate further research on ferroptosis in AKI.

Cuproptosis, a newly defined cell death process, represents a novel modality with significant therapeutic potential in cancer treatment. Nevertheless, the modest concentration and transient half-life of copper ions in the bloodstream constrain their efficient delivery into tumor cells. In this study, a copper-based prussian blue nanostructure loaded with serine metabolic inhibitor (NCT-503@Cu-HMPB) is constructed for selectively inducing cuproptosis combined with disrupting serine metabolism. Released within the tumor cells, NCT-503 is found to inhibit cellular serine metabolism and GSH production, ultimately causing metabolic dysfunction, redox imbalance, and increased the formation of Cu+ that disrupts mitochondrial respiration chain, inducing lipoylated protein dihydrolipoamide S-acetyltransferase (DLAT) aggregation and consequential iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately results in cell death. The findings provide a novel paradigm for tumor therapy based on cuproptosis and metabolic reprogramming, offering prospects for the development of innovative nanotherapeutic platforms in the future.

Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis. Extra intracellular Cu induces cuproptosis and chemodynamic therapy (CDT), which further cascades immunogenic cell death (ICD) and activates antitumor immune responses. However, the tumor immunosuppressive microenvironment (TIM) attenuates the efficiency of the immune response. Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane. ECNM can overcome the typical drawbacks of ES, ameliorating the stability and half-life of ES by membrane-coating and enhancing its tumor accumulation and internalization via homotypic targeting. It is worth mentioning that, the addition of NLG919 is also beneficial to the system circulation stability of ES and reduces the non-specific ES release. After internalization, ECNM dissociates via the glutathione-responsive process and exhibits comprehensive antitumor capabilities, including cuproptosis, CDT and TIM reversing, thereby eliciting ICD and optimizing the antitumor immune response. Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment.

Currently, the study of cuproptosis focuses on the Cu2+-induced morphology changes in mitochondria (Mito), and the observation of the effect of endoplasmic reticulum (ER)-related Cu2+ content on cuproptosis is relatively lacking. Herein, we have developed a hydroxyflavone (HF)-based NIR excited two-photon fluorescent probe, BHCO, that exhibits specific recognition of Cu2+ with high resolution. BHCO-Cu2+ (Cu2BC) can lead to DLAT protein aggregation, triggering cuproptosis. Furthermore, Cu2BC can upregulate reactive oxygen species (ROS) under 720 nm excitation, which facilitates ferroptosis. The synergistic effect of ferroptosis and cuproptosis leads to the damage of cellular mitochondria and endoplasmic reticulum, resulting in the severe death of cancer cells. We are firmly convinced that our nonlinear optical (NLO) small molecule probe for monitoring Cu2+ could provide a valid tool for rapid tumor elimination through synergistic ferroptosis and cuproptosis.

Nasopharyngeal carcinoma (NPC), one of the most common malignancies of the head and neck, is characterised by a complex pathogenesis and an unfavourable prognosis. Recently, disulfidoptosis, a novel form of cell death, has been proposed. Several studies in recent years have extensively investigated the function of the disulfidoptosis-related SLC7A11 gene in cancer, but the role of its partner protein, SLC3A2, remains unknown unclear in NPC.

GEO database analysis confirmed SLC3A2's prognostic impact on nasopharyngeal carcinoma. ROC, Kaplan-Meier analyses, and stage-specific expression studies showed a strong correlation with poor HNSC prognosis. GO and KEGG analyses pinpointed relevant signaling pathways. In vitro, SLC3A2's influence on cell proliferation, migration, and invasion was evaluated through CCK8, wound healing, colony formation, transwell assays, and cell cycle analysis.

In this study, we identified the high expression of SLC3A2 in NPC and head and neck squamous cell carcinoma (HNSC) and analyzed its potential mechanism and correlation with patient prognosis. Furthermore, a negative relationship was found between the expression level of SLC3A2 and the extent of immune cell infiltration and immune checkpoint. Differentially expressed genes (DEGs) between the high and low SLC3A2 expression groups were primarily involved in cytokine-cytokine receptor interaction and immune response. Finally, in vitro experiments demonstrated that SLC3A2 stimulates tumor cell proliferation and migration.

In conclusion, these results indicated a strong association between SLC3A2 and progression in both NPC and HNSC, suggesting it as a promising biomarker for predicting adverse prognosis in NPC and HNSC patients.

Copper, an essential trace element, is integral to numerous metabolic pathways across biological systems. In recent years, copper-based biomaterials have garnered significant interest due to their superior biocompatibility and multifaceted functionalities, particularly in the treatment of malignancies such as sarcomas and cancers. On the one hand, these copper-based materials serve as efficient carriers for a range of therapeutic agents, including chemotherapeutic drugs, small molecule inhibitors, and antibodies, allowing them for precise delivery and controlled release triggered by specific modifications and stimuli. On the other hand, they can induce cell death through mechanisms such as ferroptosis, cuproptosis, apoptosis, and pyroptosis, or inhibit the proliferation and invasion of cancer cells via their outstanding properties. Furthermore, advanced design approaches enable these materials to support tumor imaging and immune activation. Despite this progress, the full scope of their functional capabilities remains to be fully elucidated. This review provides an overview of the anti-tumor functions, underlying mechanisms, and design strategies of copper-based biomaterials, along with their advantages and limitations. The aim is to provide insights into the design, study, and development of novel multifunctional biomaterials, with the ultimate goal of accelerating the clinical application of copper-based nanomaterials in cancer therapy. STATEMENT OF SIGNIFICANCE: This study explores the groundbreaking potential of copper-based biomaterials in cancer therapy, uniquely combining biocompatibility with diverse therapeutic mechanisms such as targeted drug delivery and inhibition of cancer cells through specific cell death pathways. By enhancing tumor imaging and immune activation, copper-based nanomaterials have opened new avenues for cancer treatment. This review examines these multifunctional biomaterials, highlighting their advantages and current limitations while addressing gaps in existing research. The findings aim to accelerate clinical applications of these materials in the field of oncology, providing valuable insights for the design of next-generation copper-based therapies. Therefore, this work is highly relevant to researchers and practitioners focused on innovative cancer treatments.

Ankylosing spondylitis (AS) is a chronic autoimmune disease characterized by inflammation of the sacroiliac joints and spine. Cuproptosis is a newly recognized copper-induced cell death mechanism. Our study explored the novel role of cuproptosis-related genes (CRGs) in AS, focusing on immune cell infiltration and molecular clustering.

By analyzing the peripheral blood gene expression datasets obtained from GSE73754, GSE25101, and GSE11886, we identified the expression patterns of cellular factors and immune infiltration cell related to cuproptosis. Subsequently, we employed weighted gene co-expression network analysis (WGCNA) to identify differentially expressed genes (DEGs) within each cluster and utilized the "GSVA" and "GSEABase" software packages to examine variations in gene sets enriched across various CRG clusters. Finally, we selected the best-performing machine learning model to predict genes associated with AS. Datasets (GSE25101 and GSE73754) and ELISA to assess the expression levels of the five genes and their corresponding proteins.

Seven cuproptosis-related DEGs and four immune cell types were identified, revealing significant immune heterogeneity in the immune cell infiltration between the two cuproptosis-related molecular clusters in AS. The eXtreme Gradient Boosting (XGB) model showed the highest predictive accuracy, achieving an area under the receiver operating characteristic curve (AUC) of 0.725, and 5-gene prediction models were established. It showed satisfactory performance in the GSE25101 dataset (AUC = 0.812). According to the blood serum samples of AS patients and controls, PELI1 had a higher expression level (AUC = 0.703, p = 0.07), while ICAM2 and RANGAP1 had lower expression levels (AUC = 0.724, 0.745, and p = 0.011, 0.000, respectively) in AS patients.

We explored the correlation of cuproptosis in AS, and developed the optimal machine learning model to identify high-risk genes associated with AS. We also explored the pathogenesis and treatment strategies of AS, targeting PELI1, ICAM2, and RANGAP1.

Thyroid cancer (THCA) is an increasingly common malignant tumor of the endocrine system, with its incidence rising steadily in recent years. For patients who experience recurrence or metastasis, treatment options are relatively limited, and the prognosis is poor. Therefore, exploring new therapeutic strategies has become particularly urgent. This study confirmed that effective suppression of THCA cell proliferation and stimulation of apoptosis can be achieved through the application of Ginsenosides-Rh2. Through network pharmacology screening, the molecular target of Ginsenosides-Rh2 in THCA was identified as CHEK1, and its inhibitory effect was confirmed by downregulating CHEK1 protein expression. Furthermore, demonstrations conducted both in vitro and in vivo showcased that delivering Ginsenosides-Rh2 using nanoparticle carriers significantly reduced cell viability by approximately 50%, regulated DNA damage levels, apoptosis-related protein expression, and cell cycle control. The IC50 of the nanoparticle formulation was determined (B-CPAP IC50 = 88.24 μM), TPC IC50 = 79.52 μM). This study confirmed that Cu2O@G-Rh2 is effective in suppressing tumors and exhibits a significant inhibitory effect on tumor recurrence and metastasis while maintaining good safety. Cu2O@G-Rh2 nanoparticles possess excellent stability and anti-tumor efficacy. This research offers new perspectives for the treatment of THCA and demonstrates potential clinical applications.

Breast cancer is the most commonly diagnosed cancer worldwide. Metal metabolism is pivotal for regulating cell fate and drug sensitivity in breast cancer. Iron and copper are essential metal ions critical for maintaining cellular function. The accumulation of iron and copper ions triggers distinct cell death pathways, known as ferroptosis and cuproptosis, respectively. Ferroptosis is characterized by iron-dependent lipid peroxidation, while cuproptosis involves copper-induced oxidative stress. They are increasingly recognized as promising targets for the development of anticancer drugs. Recently, compelling evidence demonstrated that the interplay between ferroptosis and cuproptosis plays a crucial role in regulating breast cancer progression. This review elucidates the converging pathways of ferroptosis and cuproptosis in breast cancer. Moreover, we examined the value of genes associated with ferroptosis and cuproptosis in the clinical diagnosis and treatment of breast cancer, mainly outlining the potential for a co-targeting approach. Lastly, we delve into the current challenges and limitations of this strategy. In general, this review offers an overview of the interaction between ferroptosis and cuproptosis in breast cancer, offering valuable perspectives for further research and clinical treatment.

Copper is an essential micronutrient involved in various physiological processes in various cell types. Consequently, dysregulation of copper homeostasis-either excessive or deficient-can lead to pathological changes, such as heart failure (HF). Recently, a new type of copper-dependent cell death known as cuproptosis has drawn increasing attention to the impact of copper dyshomeostasis on HF. Notably, copper dyshomeostasis was associated with the occurrence of HF. Hence, this review aimed to investigate the biological processes involved in copper uptake, transport, excretion, and storage at both the cellular and systemic levels in terms of cuproptosis and HF, along with the underlying mechanisms of action. Additionally, the role of cuproptosis and its related mitochondrial dysfunction in HF pathogenesis was analyzed. Finally, we reviewed the therapeutic potential of current drugs that target copper metabolism for treating HF. Overall, the conclusions of this review revealed the therapeutic potential of copper-based therapies that target cuproptosis for the development of strategies for the treatment of HF.

Activating multiple anti-cancer pathways has great potential for tumor treatment. Herein, we synthesized two binuclear Cu(II) hydrazone complexes ([Cu2(HL1)2Cl2] 1 and [Cu2(HL1)2Br2] 2) and two mononuclear hydrazone-Cu(II) complexes ([Cu(HL2)Cl]·CH3OH 3 and [Cu(HL2)(H2O)Br]·2H2O 4), to evaluate their anti-lung cancer activities. MTT assays revealed that the Cu(II) complexes demonstrate superior anticancer activity compared to cisplatin. Among them, complex 3 exhibited selective toxicity towards A549 cancer cells in comparison to normal cells and demonstrated hemolytic activity comparable to cisplatin. The low toxicity and effective antitumor capabilities of complex 3 have been confirmed in xenograft experiments using A549 tumor-bearing mice. Interestingly, complex 3 eradicates lung tumor cells both in vivo and in vitro by initiating multiple anticancer pathways, including cuproptosis. Our research extends the study of hydrazone copper complexes and provides strategies for the treatment of lung cancer.

Exposure to metal mixtures compromises the immune system, with the complement system connecting innate and adaptive immunity. Herein, we sought to explore the relationships between blood cell metal mixtures and the third and fourth components of serum complement (C3, C4). A total of 538 participants were recruited in November 2017, and 289 participants were followed up in November 2021. We conducted a cross-sectional analysis at baseline and a longitudinal analysis over 4 years. Least Absolute Shrinkage and Selection Operator (LASSO) was employed to identify the primary metals related to serum C3, C4; generalized linear model (GLM) was further used to evaluate the cross-sectional associations of the selected metals and serum C3, C4. Furthermore, participants were categorized into three groups according to the percentage change in metal concentrations over 4 years. GLM was performed to assess the associations between changes in metal concentrations and changes in serum C3, C4 levels. At baseline, each 1-unit increase in log10-transformed in magnesium, manganese, copper, rubidium, and lead was significantly associated with a change in serum C3 of 0.226 (95% CI: 0.146, 0.307), 0.055 (95% CI: 0.022, 0.088), 0.113 (95% CI: 0.019, 0.206), - 0.173 (95% CI: - 0.262, - 0.083), and - 0.020 (95% CI: - 0.039, - 0.001), respectively. Longitudinally, decreased copper concentrations were negatively associated with an increment in serum C3 levels, while decreased lead concentrations were positively associated with an increment in serum C3 levels. However, no metal was found to be primarily associated with serum C4 in LASSO, so we did not further explore the relationship between them. Our research indicates that copper and lead may affect complement system homeostasis by influencing serum C3 levels. Further investigation is necessary to elucidate the underlying mechanisms.

In the past decade, evidence for the numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson's disease, which paved the way for novel approaches to their treatment. The discovery of cuproptosis and the role of Cu in cell metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism and in cell functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.

Dysregulation of copper metabolism is intricately associated with the occurrence and therapeutic management of colorectal cancer. Previous studies have attempted to induce cuproptosis by delivering lethal doses of copper ions into tumor cells, often with systemic safety risks. In vivo, transformable peptide is modular and designed for various tumor-related proteins, which can affect protein function and distribution. Here, a fibrillar transformation peptidic (FTP) nanoparticle is synthesized, which can bind ATP7B membrane proteins (cuprous ions transporter) and transform into nanofibrils/ATP7B clusters, inducing "copper-free cuproptosis" in vivo. Without adding exogenous copper ions, the spherical FTP nanoparticles bound the high distribution regions of ATP7B membrane proteins, transforming into fibrillar networks in situ with prolonged retention. The cage-like fibrillar network would further capture unbound or newly generated free ATP7B membrane proteins, thereby significantly and consistently preventing cuprous ions efflux. The FTP nanoparticles would not undergo in situ fibrillar transformation on the low expression region of ATP7B membrane proteins but enter the cell for safe degradation, which exhibited high specificity and safety in vivo. By disrupting intracellular copper homeostasis, the transformable fibrillar clusters displayed a long-term anti-tumor effect on subcutaneous transplantation and liver metastatic CRC models.

Hepatic ischemia-reperfusion injury (HIRI) is a common injury not only during liver transplantation but also during major hepatic surgery. HIRI causes severe complications and affects the prognosis and survival of patients. Cuproptosis, a newly identified form of cell death, plays an important role in a variety of illnesses. However, its role in HIRI remains unknown.

The GSE151648 dataset was mined from the Gene Expression Omnibus (GEO) database, and differences were analyzed for intersections. Based on the differentially expressed genes (DEGs), functional annotation, differentially expressed cuproptosis-related genes (DE-CRGs) identification and lasso logistic regression were conducted. Correlation analysis of DE-CRGs and immune infiltration was further conducted, and DE-CRGs were applied to construct an HIRI diagnostic model. The hierarchical clustering method was used to classify the specimens of HIRI, and functional annotation was conducted to verify the accuracy of these DE-CRGs in predicting HIRI progression. The GSE14951 microarray dataset and GSE171539 single-cell sequencing dataset were chosen as validation datasets. At the same time, the significance of DE-CRGs was verified using a mouse model of HIRI with cuproptosis inhibitors and inducers. Finally, a network of transcription-factor-DE-CRGs and miRNA-DE-CRGs was constructed to reveal the regulation mechanisms. And potential drugs for DE-CRGs were predicted using Drug-Gene Interaction Database (DGIdb).

Overall, 2390 DEGs and 19 DE-CRGs were identified. Through machine learning algorithms, 8 featured DE-CRGs (GNL3, ALAS1, TSC22D2, KLF5, GTF2B, DNTTIP2, SLFN11 and HNRNPU) were screened, and 2 cuproptosis-related subclusters were defined. Based on the 8 DE-CRGs obtained from the HIRI model [area under the curve (AUC)=0.97], the nomogram model demonstrated accuracy in predicting HIRI. Eight DE-CRGs were highly expressed in HIRI samples and were negatively related to immune cell infiltration. A higher level of immune infiltration and expression of CRG group B was found in the HIRI population. Differences in cell death and immune regulation were found between the 2 groups. The diagnostic value of the 8 DE-CRGs was confirmed in the validation of two datasets. The identification of 7 DE-CRGs (SLFN11 excluded) by HIRI animal model experiments was also confirmed. Using hTFtarget, miRWalk and DGIDB database, we predicted that 17 transcription factors, 192 miRNAs and 10 drugs might interact with the DE-CRGs.

This study shows that cuproptosis may occur in HIRI and is correlated with immune infiltration. Additionally, a cuproptosis-related predictive model was constructed for studying the causes of HIRI and developing targeted treatment options for HIRI.

Approximately one-tenth of the global population is affected by diabetes mellitus, and its incidence continues to rise each year. In China, 1.4 million patients die from diabetes-related complications every year. Additionally, approximately 26% of patients with diabetes develop diabetic cardiomyopathy, with heart failure being one of the main causes of death in these patients. However, early detection of diabetic cardiomyopathy has proven to be difficult in a clinical setting; furthermore, there are limited guidelines and targeted means of prevention and treatment for this disease. In recent years, several studies have provided evidence for the occurrence of various forms of regulated cell death in diabetic myocardial cells, including apoptosis, necroptosis, ferroptosis, and cuproptosis, which are closely linked to the pathological progression of diabetic cardiomyopathy. Although most research on diabetic cardiomyopathy is currently in the animal trial phase, the inhibition of these regulatory cell death processes can limit or slow down the progression of diabetic cardiomyopathy. Therefore, this review discusses the appropriate animal experimental models currently available for diabetic cardiomyopathy and evaluates the roles of apoptosis, necroptosis, ferroptosis, and cuproptosis in diabetic cardiomyopathy. We hope to provide new methods and ideas for future research in diabetic cardiomyopathy.