The aberrations in copper metabolism and their implications in neoplasms have generated increasing interest from the global scientific community[2, 3, 9]. Elevated copper levels have now been found implicated in various malignancies, such as breast, colorectal, lung and gallbladder cancers [10–13].
However, due to the unstable chemical properties and tissue-specific effects of copper, research on copper homeostasis in the context of neoplasms is encountering significant challenges. A bibliometrics analysis on copper homeostasis in neoplasms would be essential to synthesize impactful articles and forecast potential future directions for scientists. To the best of current knowledge, this study was the first bibliometrics analysis assessing the productivity in the biomedical science of copper homeostasis in neoplasms, based on the global data to cue the major scientific prevalence and with a strategic coordinate map to suggest the potential stimulating trends.
This investigation conducted a thorough and descriptive bibliometrics analysis of 1701 publications on copper homeostasis in neoplasms from 2013 to 2023. This field has garnered intense scholarly attention from China, the United States, and India, all of which also have engaged in varying degrees of international cooperation. The United States and India exhibited the highest multiple-country publications ratios and substantial publication volume, indicating their strong potential and willingness for international partnerships.
China, while having a high publication volume, showed a surprisingly lower multiple-country publications ratio, suggesting that its domestic collaborations were extensive and yielded satisfactory quantitative and qualitative outcomes. This was further illustrated by the visualization of institutions, where over half of the universities in the collaboration network graph were from China. Institutions such as the Chinese Academy of Sciences, Sichuan Agricultural University, Sichuan University, Shanghai Jiao Tong University and Sun Yat-sen University emerged as prominent sources of citations and references.
Consistent with the previous findings, the most cited reference covered the advances in copper complexes as anticancer agents, highlighting the pivotal role of copper in angiogenesis [14].
The most productive journal with high-quality and cutting-edge articles, the Journal of Inorganic Biochemistry, was most likely to provide essential sources for fundamental knowledge of copper homeostasis in neoplasms, which also would be a good choice to submit research.
Two of the top 10 most-cited references were from Nature, underscoring its capability to identify high-level articles in this field. One study from Nature proposed the repurposing of Cu-chelation therapy for treating cancers with the BRAFV600E mutation[15]. Another study from Nature identified the ditiocarb–copper complex as the active metabolite of disulfiram responsible for its anti-cancer effects, offering methods to detect preferential accumulation of the complex in tumors and candidate biomarkers to analyze its impact on cells and tissues[16].
The historical hotspots of copper homeostasis in neoplasms were synthesized to forecast the scientific trends based on the keyword analysis of high-impact articles, suggesting copper’s influence on the development of various solid organ tumors through tumor microenvironment, gene expression, and cell death, particularly associated with liver cancer.
Keywords elucidate crucial aspects of the literature and highlight the research foci. Analyzing the frequency and clustering of keywords over time would reveal the shifting priorities and research interests across different periods[17]. The domains of curprotosis, diagnosis methodologies, and hepatocellular carcinoma were well-established research areas. It has been demonstrated that quantifying copper levels and fluctuations in the bloodstream may be a more reliable indicator for tumor staging compared to copper concentrations in tissues[18, 19]. Concurrently, these assessments would likely necessitate the combined evaluation of other heavy metals, such as selenium and zinc[20].
The thematic map may further elucidate the evolution of dominant themes in copper homeostasis in neoplasms. The concepts of cuprotosis, prognosis, hepatocellular carcinoma, anticancer and anticancer activity were recognized as pivotal motor themes within this field. As the center for copper storage and transport, the liver plays a systemic regulator in regulating copper homeostasis[21]. Copper metabolism influences hepatocellular carcinogenesis and metastasis, including autophagy, apoptosis, vascular invasion, cuproptosis and ferroptosis[22]. On March 17, 2022, Tsvetkov et al. introduced a novel copper-dependent cell death mechanism termed “cuprotosis”, distinct from other known cell death pathways such as apoptosis, pyroptosis, and necroptosis. Analogous to zinc-induced death and ferroptosis, cuprotosis is a form of metal ion-induced regulated cell death[23–26]. In his studies, a cuprotosis correlation prediction model was significantly associated with the prognosis of pancreatic cancer patients[23].
Historically, platinum-based chemotherapeutics (e.g., cisplatin) have been highly effective as cancer therapeutics, however, their usages were constrained by adverse effects and resistance[2, 14]. Thus, it would be pertinent to explore the therapeutic potential of more relevant endogenous metals like copper. Targeting copper metabolism would enhance the efficacy of chemopreventive and anticancer agents[27, 28]. Copper chelating to reduce copper bioavailability has remained under investigation in clinical studies to inhibit angiogenesis across various cancer types[3]. Another study has tried to develop a cuprotosis signature risk score to accurately predict the survival, immunity, and subtype of gastric cancer[29].
Heavy metals, cancer risk and health risk assessment have emerged as the niche terms warranting further investigation. Previous studies have significantly demonstrated that cancer patients tended to have higher copper levels than healthy individuals[30]. Mechanistic studies are needed to further elucidate the role of elevated copper and copper/zinc ratio levels in the development and progression of colon tumors.
The basic themes essential for transdisciplinary endodontic research issues included cancer, zinc, oxidative stress, cytotoxicity and apoptosis, which are critical for a comprehensive understanding of this field. Zinc has demonstrated anticancer efficacy against non-small-cell lung cancer cells in the presence of functionally active p53 and enhances docetaxel efficacy in both p53-wild-type and p53-deficient cancer cells[31]. A European prospective investigation into cancer and nutrition cohort indicated that the copper-to-zinc ratio would become imbalanced during colorectal cancer development[10, 32]. Evidence has established copper as a tumor promoter and revealed that varying copper levels would regulate oxidative phosphorylation in rapidly proliferating cancer cells within solid tumors[33]. Consequently, activation of glycolysis in tumors may partially reflect insufficient copper bioavailability in the tumor microenvironment[33].
The emerging themes included antioxidant, immunity, copper complexes and cytotoxic activity, which show potential to become central motor themes, though underdeveloped. One study suggested that copper complexes could be effective in treating prostate cancer patients resistant to traditional androgen ablation therapies[34]. Another review predicted that the detailed mechanistic insights, including identifying sensitive biological targets involved in the antiproliferative activity of copper complexes would contribute to a more rational design of ‘‘second-generation’’ copper drugs[9].
This study delineated the advancements in copper homeostasis in neoplasms but still had some limitations. One limitation was the inclusion of various document types beyond peer-reviewed articles, such as conference abstracts, which were indexed with insufficient details. The predominance of basic science articles in the research output indicated a relatively low level of evidence. Studies with higher levels of evidence are warranted to strengthen future research.