Ferroptosis—The “Double-Edged Sword” in Cancer - Mechanisms of Tumor Suppression/Resistance and Therapeutic Manipulation

Sep 30, 2026

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Ferroptosis is a non-apoptotic, iron-dependent cell death driven by the buildup of membrane lipid peroxides. Its execution is governed by interconnected processes, including redox homeostasis, the intracellular labile iron pool, and amino acid metabolism. In cancer, ferroptosis can operate in opposite directions, supporting tumor progression or tumor suppression. Promoting ferroptosis in cancer cells can yield tumor-suppressive effects but may impair anticancer immunity, enabling growth. Cells resistant to apoptosis can remain vulnerable, making ferroptosis a therapeutic lever for induction or inhibition.

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CategoryHealthcare

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Review Ferroptosis—The “Double-Edged Sword” in Cancer: Mechanisms of Tumor Suppression/Resistance and Therapeutic Manipulation Danielle Quaranto 1,*, Nicole R. DeSouza 1, Michelle Carnazza 2, Augustine Moscatello 3, Humayun K. Islam 1, Xiu-Min Li 1,3,4, Raj K. Tiwari 1,3 and Jan Geliebter 1,3, * Academic Editor: Abdel Ali Belaidi Received: 25 November 2025 Revised: 23 December 2025 Accepted: 25 December 2025 Published: 30 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA 2 Department of Research & Development, General Nutraceutical Technology, LLC, Briarcliff Manor, NY 10510, USA 3 Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA 4 Department of Dermatology, New York Medical College, Valhalla, NY 10595, USA * Correspondence: [dquarant@student.touro.edu](dquarant@student.touro.edu) (D.Q.); [jan_geliebter@nymc.edu](jan_geliebter@nymc.edu) (J.G.) Simple Summary Cell death is a process that can occur in cancerous cells in a variety of forms. Ferroptosis is a type of cell death that occurs when there is an overload of iron within the cell, leading toa disruption in vital components of the cellular membrane. In cancer, ferroptosis can play a“double-edged sword” role, where it can be either beneficial or detrimental. There are several factors of ferroptosis that can either promote or prevent cancer from occurring. These factors contribute to pathways that allow it to be studied and manipulated therapeutically for the benefit of treating cancer. Abstract Ferroptosis is a non-apoptotic, iron-dependent form of cell death. The characteristic accumulation of membrane lipid peroxides that occurs is controlled by several different mechanisms including redox homeostasis, the intracellular labile iron pool, and amino acid metabolism. In cancer, ferroptosis can contribute to either tumor progression or tumor suppression. When promoted in cancer cells, ferroptosis plays an innately tumor-suppressiverole; however, it can negatively affect anticancer immunity, allowing for tumor growth and progression. Cells that are traditionally known to be resistant to apoptosis and other forms of cell death have demonstrated susceptibility to ferroptosis, making this form of cell death particularly useful in terms of cancer therapeutics. This narrative review will focus on the role of ferroptosis in cancer promotion or prevention and how it can be manipulated therapeutically—whether it be induced or inhibited. Keywords: ferroptosis; cancer; iron homeostasis 1. Introduction Ferroptosis is an iron-dependent form of programmed cell death that is driven by the accumulation of reactive oxygen species (ROS), leading to the formation of membranedamaging lipid peroxides [1] . This form of cell death is considered to be distinct from other forms, such as apoptosis, pyroptosis, and necroptosis, in both morphological and mechanistic ways [2] . Morphologically, cells undergoing ferroptosis exhibit several changes in their mitochondria, including smaller size, decreased cristae, and much more condensed membranes [3] . Mechanistically, ferroptosis has yet to be identified as being initiated by executioner proteins, as is seen in many other forms of cell death [4] . Overall, cells undergoing ferroptosis appear to have a reduced cell volume, with a characteristic loss of membrane integrity [5] . The overall process of ferroptosis includes the accumulation of ferrous iron, free radical production, dysfunction of the antioxidant system, and membranebound lipid peroxide formation [6] . The execution of ferroptosis is classified as the oxidation of phospholipids containing polyunsaturated fatty acids (PUFAs) [7] . Dixon et al. were among

FAQs

What is ferroptosis, and what makes it distinct from other cell death types?

Ferroptosis is a non-apoptotic, iron-dependent programmed form of cell death characterized by accumulation of membrane lipid peroxides. It is driven by processes tied to iron metabolism and lipid oxidation rather than being suppressible by classic caspase or necroptosis inhibitors.

How can ferroptosis contribute to both tumor suppression and tumor progression?

In cancer, ferroptosis can be promoted to create tumor-suppressive effects, yet it can also negatively influence anticancer immunity and thereby support tumor growth and progression. This makes its overall role context-dependent and paradoxical.

Why is ferroptosis considered relevant for cancer therapeutics?

Cancer cells traditionally resistant to apoptosis may still be susceptible to ferroptosis, creating a potential therapeutic vulnerability. The review emphasizes that ferroptosis pathways can be manipulated either to induce or inhibit ferroptosis for different cancer outcomes.

Sep 30, 2026

Uploaded by Finn