Copper, cuproptosis, and cancer - biology concepts of a novel cell death

Sep 22, 2026

Copper is an essential trace element for mitochondrial respiration, redox control, iron metabolism, and cellular signalling, yet excess or mislocalized copper becomes cytotoxic. Cuproptosis is a newly defined regulated cell death where copper binds lipoylated mitochondrial proteins, triggering their aggregation, iron–sulfur cluster protein destabilisation, and mitochondrial proteotoxic stress. In cancer, copper can support tumor metabolism and angiogenesis, while therapeutic depletion or copper ionophores can induce cuproptosis in susceptible cells. The review maps copper homeostasis and molecular determinants of vulnerability.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Abstract

Introduction

Copper and cuproptosis mechanisms

Therapeutic implications

Apoptosis (2026) 31:223 [https://doi.org/10.1007/s10495-026-02432-w](https://doi.org/10.1007/s10495-026-02432-w) REVIEW Copper, cuproptosis, and cancer: biology concepts of a novel cell death Reza Eshraghi1 · Nastaran Hosseini2 · Mohammad Sepehr Yazdani3 · Shirin Badihi2 · Pedram Pirmoradian2 · Ashkan Bahrami2 · Bahar Darouei2 · Shayan Ghanouni2 · Alfred K. Lam4,5 · Michael R. Hamblin6 Received: 26 May 2026 / Accepted: 18 August 2026 / Published online: 3 September 2026 © The Author(s) 2026 Abstract Copper is an essential trace element required for mitochondrial respiration, redox regulation, iron metabolism, and cellular signalling, but excessive or mislocalised copper can be cytotoxic. Cuproptosis is a recently identified form of regulated cell death in which copper binds to lipoylated mitochondrial proteins, promotes their aggregation, destabilises iron–sulfur cluster proteins, and induces mitochondrial proteotoxic stress. Copper therefore has context-dependent roles in cancer. Physiological copper supports tumour metabolism, angiogenesis, extracellular-matrix remodelling, and selected oncogenic signalling pathways, whereas therapeutic copper depletion can inhibit copper-dependent tumour processes. Conversely, copper ionophores and related approaches may increase intracellular copper sufficiently to induce cuproptosis in metabolically susceptible cancer cells. This review describes systemic and intracellular copper homeostasis, including intestinal absorption, intracellular trafficking, mitochondrial copper distribution, storage, and export. Particular attention is given to CTR1/SLC31A1, the functionally distinct copper-transporting ATPases ATP7A and ATP7B, metallothioneins, copper chaperones, and cytochrome c oxidase assembly factors. We also examine how cancer cells reprogramme copper handling to support proliferation, angiogenesis, metastasis, and immune evasion. Finally, we discuss the molecular basis of cuproptosis, including the roles of FDX1, FDXR, LIAS, DLAT, mitochondrial respiration, protein lipoylation, and iron–sulfur cluster destabilisation. Current evidence indicates that cuproptosis susceptibility varies among tumour types and depends on copper handling, mitochondrial metabolic state, and the integrity of the protein-lipoylation machinery. Defining these determinants will be necessary for the development of tumour-selective copper-targeted therapies. Reza Eshraghi[eshraghi.rza@gmail.com](eshraghi.rza@gmail.com) Michael R. Hamblin [hamblin.lab@gmail.com](hamblin.lab@gmail.com) Nastaran Hosseini [Nastaran.h97@gmail.com](Nastaran.h97@gmail.com)[ ](Nastaran.h97@gmail.com)Mohammad Sepehr Yazdani [mr.msyazdani@gmail.com](mr.msyazdani@gmail.com) Shirin Badihi [shirinbadihi78@gmail.com](shirinbadihi78@gmail.com)[ ](shirinbadihi78@gmail.com)Pedram Pirmoradian [pedrampirmoradiaan@gmail.com](pedrampirmoradiaan@gmail.com)[ ](pedrampirmoradiaan@gmail.com)Ashkan Bahrami [ashkanbahrami1998@gmail.com](ashkanbahrami1998@gmail.com)[ ](ashkanbahrami1998@gmail.com)Bahar Darouei [bahar.daruei@gmail.com](bahar.daruei@gmail.com) Shayan Ghanouni [sghanouni@yahoo.com](sghanouni@yahoo.com) Alfred K. Lam [a.lam@griffith.edu.au](a.lam@griffith.edu.au) 1 Social Determinants of Health Research Center, Isfahan University of Medical Sciences, Daneshgah Bvld, Isfahan 8174673441, Iran 2 School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 3 School of Medicine, Kashan University of Medical Sciences, Isfahan, Iran 4 School of Medicine and Dentistry, Griffith University, Gold Coast Campus, Southport, Gold Coast, QLD 4222, Australia 5 Pathology Queensland, Gold Coast University Hospital, Southport, Gold Coast, QLD 4215, Australia 6 Faculty of Health Science, Laser Research Centre, University of Johannesburg, Doornfontein 2028, South Africa Graphical abstract Keywords Cuproptosis · Copper homeostasis · Copper · Cancer treatment · Mitochondrial dysfunction Introduction Coppe

FAQs

Why can copper become cytotoxic in cells?

Copper is required for key processes, but excessive amounts or mislocalisation can produce cytotoxic effects, disrupting cellular functions.

What defines cuproptosis compared with other regulated cell death pathways?

Cuproptosis is strongly linked to mitochondrial metabolism and is triggered by excessive intracellular copper binding to lipoylated mitochondrial proteins, leading to aggregation and iron–sulfur cluster protein destabilisation.

How can targeting copper affect cancer therapy?

Physiological copper may support tumor growth and processes like angiogenesis, whereas therapeutic copper depletion or copper ionophores can inhibit copper-dependent tumour activities or induce cuproptosis in susceptible cancer cells.

Sep 22, 2026

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