Cuproptosis: molecular mechanisms, cancer prognosis, and therapeutic applications

Cong et al. Journal of Translational Medicine https://doi.org/10.1186/s12967-025-06121-1 Journal of Translational Medicine (2025) 23:104 Open Access REVIEW Cuproptosis: molecular mechanisms, cancer prognosis, and therapeutic applications Yating Cong1 , Na Li1,2, Zixin Zhang1, Yan Shang1 and Hailong Zhao1* Abstract Cuproptosis differs from other forms of cell death, such as apoptosis, necroptosis, and ferroptosis, in its unique molecular mechanisms and signaling pathways. In this review, we delve into the cellular metabolic pathways of copper, highlighting the role of copper in biomolecule synthesis, mitochondrial respiration, and antioxidant defense. Furthermore, we elucidate the relationship between cuproptosis-related genes (CRGs) and cancer prognosis, analyzing their expression patterns across various tumor types and their impact on patient outcomes. Our review also uncovers the potential therapeutic applications of copper chelators, copper ionophores, and copper-based nanomaterials in oncology. In addition, we discuss the emerging role of cuproptosis in remodeling the tumor microenvironment, enhancing immune cell infiltration, and converting “cold tumors” into “hot tumors” that respond better to immunotherapy. In short, this review underscores the pivotal importance of cuproptosis in cancer biology and highlights its translational potential as a novel therapeutic target. Keywords Cuproptosis, Copper metabolism, Cancer prognosis, Immunotherapy Introduction In recent years, the scientific community has witnessed a surge of interest in elucidating the diverse mechanisms underlying cell death, a fundamental biological process essential for tissue homeostasis and disease progression. Among the various modalities of programmed cell death, cuproptosis has emerged as a novel and intriguing concept, distinct from well-established pathways such as apoptosis, necroptosis, and ferroptosis. The discovery of cuproptosis by Tsvetkov et al. in 2022 highlights the complex interplay between copper ions and cellular metabolism, uncovering a new dimension in our understanding of cell demise. *Correspondence: Hailong Zhao 1 Department of Pathophysiology, Zunyi Medical University, Zunyi, Guizhou 563000, China 2 The First Clinical Institute, Zunyi Medical University, Zunyi, Guizhou 563000, China Copper, an essential trace element in the human body, plays crucial roles in biomolecule synthesis, mitochondrial respiration, and antioxidant defense. However, excess copper can disrupt cellular homeostasis, leading to the induction of cuproptosis. This form of cell death is characterized by the aggregation of lipoylated proteins in the tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and ultimately triggering mitochondrial dysfunction and cell death. The discovery of cuproptosis has significant implications for cancer biology and therapeutics. Cancer cells, known to have a higher copper dependency compared to normal cells, may be particularly susceptible to cuproptosis-inducing agents. This finding underscores the potential of targeting copper metabolism as a novel therapeutic strategy for cancer treatment. In this review, we aim to provide a comprehensive overview of cuproptosis, delving into its molecular mechanisms, signaling pathways, and relationship with cancer prognosis. Furthermore, we will discuss the emerging © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Cong et al. Journal of Translational Medicine (2025) 23:104 therapeutic applications of cuproptosis, focusing on copper chelators, copper ionophores, and copper-based nanomaterials that have shown promise in inducing cuproptosis and inhibiting tumor growth. By elucidating the underlying biology of cuproptosis and its potential therapeutic value, we hope to stimulate further research in this exciting field and contribute to the development of innovative cancer treatments [1,2]. Molecular mechanisms of copper Page 2 of 17 ceruloplasmin is responsible for distributing copper from the liver to other tissues and organs. The liver effectively eliminates excess copper through biliary excretion or by releasing metal ions into the feces. Other excretory routes, such as urine, sweat, and menstrual fluid, contribute minimally to copper excretion. Consequently, systemic copper homeostasis is primarily maintained through duodenal absorption and biliary excretion [5] (Fig. 1). Copper homeostasis and transport Copper absorption, distribution, and excretion Copper is an essential trace element required by nearly all living organisms, predominantly sourced from solid food and drinking water. Serving as a crucial cofactor, copper is naturally abundant in organ meats, shellfish, seeds, legumes, vegetables, and whole grains. Additionally, industrial products can influence copper intake [3]. The human body contains an estimated 100 to 150 milligrams of copper, distributed across various tissues, including the brain, skin, and others, with predominant concentrations in the liver, muscles, and bones [4]. The distribution of copper within the body occurs in two distinct phases [Owen, 1971]. During Phase I, albumin and transferrin facilitate the transportation of copper to the liver and kidneys. Subsequently, in Phase II, The human body primarily absorbs copper in the duodenum and small intestine, facilitated mainly by the Cu transport protein 1 (CTR1), which is positioned at the apical membrane of intestinal epithelial cells [6]. This uptake process is also associated with the reduction of divalent Cu2+ to monovalent Cu+ by enzymes such as sixtransmembrane epithelial antigen of prostate (STEAP) and duodenal cytochrome b(DCYTB) [7]. The CTR1 protein exhibits a conserved three-domain topology akin to members of the SLC31 family, featuring an amino-terminal exo-structural domain rich in Cu(I)-binding histidine and methionine sequences, along with three transmembrane domains. Biochemical studies reveal that SLC31 family members assemble into fun (...truncated)