Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials

Abstract

Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings.

Muscle-invasive bladder cancer subtyping and prognosis: a multi-omics study based on a ferroptosis and cuproptosis-related signature

“…The interplay between two forms of cell death, ferroptosis and cuproptosis, has garnered scienti c interest. Disruptions in their metabolic functions can lead to lethal consequences for cancer cells, triggering both ferroptosis and cuproptosis [57]. The mechanism of copper-dependent cell death is closely linked to mitochondrial respiration, initiated when copper binds directly to the lipoylated components of the tricarboxylic acid (TCA) cycle [11].…”

“…This binding sets off a series of events, including protein oligomerisation, loss of iron-sulfur cluster proteins, and proteotoxic stress, leading to cell death [58]. In addition, a connection between mitochondrial copper accumulation and the initiation of ferroptosis has been established [57].…”

Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer

“…Moreover, copper metabolism is considered a promising strategy for cancer therapy [16]. Furthermore, there exists mutual dependence between cuproptosis and ferroptosis [17]. Studies have revealed that in hepatocellular carcinoma, sorafenib and erastin upregulate protein lipoylation by inhibiting degradation of iron-sulfur cluster protein 1 (FDX 1) mediated by mitochondrial matrix-related protease, and reduce synthesis of intracellular copper chelator glutathione (GSH) by inhibiting cysteine input [18].…”