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STATE OF THE ART PAPER
Metabolic alterations and redox homeostasis in ferroptosis: emerging mechanisms and therapeutic implications
1
Institute of Chemistry, Technology and Metallurgy, Center for Chemistry, National Institute of the Republic of Serbia, University of Belgrade, Serbia
2
University of Belgrade ‒ Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology and Toxicology, Belgrade, Serbia
3
Clinical Center of Montenegro, Department of Neurology, Podgorica, Montenegro
4
Institute for Oncology and Radiology of Serbia, Department of Experimental Oncology, Belgrade, Serbia
5
University of Montenegro, Faculty of Medicine, Podgorica, Montenegro
6
Center for Laboratory Diagnostics, Primary Health Care Center, Podgorica, Montenegro
These authors had equal contribution to this work
Submission date: 2026-03-21
Final revision date: 2026-05-28
Acceptance date: 2026-06-26
Online publication date: 2026-08-20
Corresponding author
Aleksandra Klisic
University of Montenegro Faculty of Medicine Center for Laboratory Diagnostics Primary Health Care Center Trg Nikole Kovacevica 6 81000 Podgorica Montenegro Phone/fax: +382 20 481 999
University of Montenegro Faculty of Medicine Center for Laboratory Diagnostics Primary Health Care Center Trg Nikole Kovacevica 6 81000 Podgorica Montenegro Phone/fax: +382 20 481 999
KEYWORDS
ferroptosisglutathione metabolismGPX4lipid metabolismiron metabolismredox homeostasiscancer therapeutics
TOPICS
ABSTRACT
Ferroptosis is a programmed cell death characterized by excessive, iron-dependent accumulation of membrane lipid peroxides due to insufficient glutathione-dependent antioxidant defense. It is influenced by the metabolism of amino acids, lipids, and iron, and occurs in conditions of decreased glutathione peroxidase 4 (GPX4) activity. The increased polyunsaturated fatty acid (PUFA) content in membrane phospholipids is associated with cellular hypersusceptibility to ferroptosis. In contrast, incorporation of monounsaturated fatty acids may protect cells against ferroptotic cell death. Cellular sensitivity to ferroptosis is additionally influenced by glutamine catabolism and the xc–system-mediated import of cystine, which modulate glutathione production, and by elevated iron levels, which lead to the buildup of reactive oxygen species (ROS) that attack membrane-localized PUFAs. This review focuses on recent findings of perturbed metabolic processes in cancer that create a high iron demand and an altered lipid composition, thereby predisposing cells to ferroptosis. We analyze the therapeutic potential of pharmacological agents that can selectively trigger ferroptosis in tumor cells.
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