Recently, the research team led by Professor Xie Liwei from the Faculty of Synthetic Biology at Shenzhen University of Advanced Technology, in collaboration with Professor Wang Fudi and Professor Min Junxia's team from the School of Basic Medical Sciences at Zhejiang University, Professor Liu Jingxia's team from the College of Fisheries at Huazhong Agricultural University, Researcher Wang Yanfang's team from the Institute of Animal Science of CAAS, and Professor Li Chenghua's team from the College of Life Sciences at Sichuan University, published a review titled"Copper and Cuproptosis:Mechanisms, Biology, and Roles in Disease"in Science Bulletin (Zone 1, Impact Factor 21). The article systematically reviews copper biology, cuprology, the regulatory mechanisms of cuproptosis and its roles in developmental abnormalities, as well as the potential translational applications in the treatment of diseases such as cancer.

Copper is one of the essential trace elements for life, yet its research history spans more than a century. In the early 20th century, scientists discovered Wilson disease (WD) caused by mutations in the ATP7B gene, characterized by copper overload in patients; in the 1960s, Menkes disease (MD) caused by ATP7A gene mutations was identified, characterized by systemic copper deficiency in peripheral tissues. As early as the 1930s, Australian scientists observed"steely wool"and"swayback”in sheep, symptoms also resulting from copper deficiency. In recent years, Chinese scientists have used mouse and zebrafish model systems to reveal the regulatory mechanisms by which copper homeostasis imbalance leads to developmental defects and diseases, achieving a series of original results with translational potential. In 2022,the team led by Peter Tsvetkovformally proposed the concept of "cuproptosis", pointing outthe innovative translational theory that "targeted killing of cancer cells dependent on mitochondrial respiration using copper ion metal carriers may become a new method for cancer treatment". It is evident thatcopper research is entering a new era of rapid development.

Comprehensive Review:Systematically Reviewing Copper Biology — Cuprology and Cuproptosis

This review systematically summarizes the regulatory roles of the trace element copper at multiple levels, including molecular, cellular, tissue, and organismal levels, covering research progress on the catalytic functions of copper-dependent enzymes, metabolic signal transduction, and organelle homeostasis. Based on the two core concepts of "cuproptosis" and "cuprology", this article systematically reviews the interdisciplinary system in copper biology that integrates molecular mechanisms, life processes, disease occurrence, and cutting-edge translational applications. In addition, the article systematically integrates basic research findings such as copper homeostasis regulation, cuproptosis molecular pathways, and cellular metabolic interaction networks, as well as cutting-edge technological breakthroughs such as copper ion carriers and precise delivery by nanocarriers, providing an in-depth explanation of the complex interactive regulatory mechanisms among copper homeostasis, the cuproptosis signaling axis, and cellular metabolism. Finally, the article systematically reviews intervention strategies targeting the copper–cuproptosis axis, aiming to provide innovative therapeutic solutions for diseases associated with copper homeostasis imbalance and to propel research on cell death and metabolic regulation into a new stage of development.

1.Review of the Research History and Hotspots in Copper Biology

This article systematically reviews the milestone research advances in copper biology over the past century and more. Starting from Wilson disease (WD), Menkes disease (MD), and symptoms such as "steely wool" in Australian sheep, researchers gradually discovered the close association between these diseases and copper homeostasis imbalance in the body.

Subsequently, copper transport-related genes were successfully identified and cloned, advancing research on the mechanisms of copper homeostasis regulation at the cellular and organismal levels. This led to the proposal of the concept "Cuprology", emphasizing the integrative significance of copper homeostasis regulation across multiple levels from molecules and cells to organs and the whole organism. Further studies revealed that copper-binding proteins and copper-allosteric proteins are associated with "stable copper pool" and the "labile copper pool" (LCP), respectively. With the aid of copper ion probes, researchers can monitor real-time changes in copper ion levels in cells or systems, and uncover how the labile copper pool triggers cuproptosis and related signaling pathways.

2. Emphasis on Cuprology:Copper Homeostasis and Organogenesis

This article systematically reviews human diseases associated with disrupted copper homeostasis caused by genetic and environmental factors (such as diet and environmental exposure). It deeply examines discoveries in disease models such as copper homeostasis-imbalanced mice and zebrafish, along with their potential regulatory mechanisms and molecular targets, highlighting the significance of integrating multi-model research findings in revealing the molecular mechanisms of neural and hematopoietic organ developmental defects under copper homeostasis imbalance.

3.Systematic Review of Copper Homeostasis Imbalance and Disease Occurrence:Neurodegenerative Diseases, Metabolic Diseases, Digestive System Diseases, and Cancer

The article systematically reviews how copper homeostasis imbalance induces diseases and the underlying molecular regulatory mechanisms. It particularly notes that when copper is excessive in brain tissue, excess labile copper is aberrantly bound by Aβ and Tau proteins, leading to decreased activity of a key enzyme called peptidylglycine α-amidating monooxygenase (PAM) (responsible for activating certain neuropeptides), thereby promoting the occurrence of neurodegenerative diseases. In addition, the article emphasizes that the labile copper pool can harm health in multiple ways, such as promoting abnormal angiogenesis, inhibiting the activity of lipolysis-related proteins, altering cellular energy metabolism, or disrupting the balance of the gut microbiota. These mechanisms may either accelerate cancer progression or trigger other diseases associated with copper metabolism imbalance.

4.Treatment of Copper-Related Diseases:Applications, Limitations, and Countermeasures

The clinical use of copper chelators to treat copper overload-induced Wilson disease, or copper supplementation agents to treat copper deficiency-induced Menkes disease, has a history of nearly 50 years. In recent years, scientists have developed nano-copper sustained-release agents, novel low-toxicity copper delivery systems, and chelators, applying them to the treatment of various diseases including cancer. However, these therapies still have certain limitations in practical application, with therapeutic efficacy varying across individuals and sexes, and often showing reduced effectiveness when translated from animal experiments to humans. Therefore, future research needs to focus on two aspects: first, deeply analyzing the metabolic characteristics and genetic features of individual patients to develop personalized treatment plans; second, further revealing the regulatory mechanisms of cuproptosis and developing "cuproptosis-inducing" therapies capable of selectively targeting mitochondrial respiration-dependent cancer cells.

Dr. Xie Liwei, Tenured Associate Professor and Distinguished Professor at the Faculty of Synthetic Biology, Shenzhen University of Advanced Technology. His research focuses on gut microbiota-mediated inter-tissue crosstalk and human health, covering systemic trace element metabolism, physiological regulatory mechanisms governing muscle and adipose stem cells, and the mechanistic and translational roles of gut microbiota-host nutrient metabolism interactions in metabolic diseases. In the past five years, he has published more than 50 high-impact research articles with over 3,000 citations. His research achievements have mainly been published in internationally recognized journals includingThe Innovation(IF: 32.2). He has been granted 6 Chinese invention patents and 4 international patents. He has received 2 General Programs, 1 Young Scientist Program, and 1 Regional Key Program from the National Natural Science Foundation of China, the Outstanding Young Scientist Fund of the Guangdong Basic and Applied Basic Research Foundation, serves as the principal investigator of a National Key R&D Program project under the Science and Technology Innovation 2030 initiative, and has secured more than RMB 4 million in industry-sponsored research funding.

Link:https://authors.elsevier.com/sd/article/S2095-9273(26)00505-0