Targeting ferroptosis in cancer: molecular mechanisms and emerging therapeutic strategies.
11 affiliations
- 1Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
- 2Department of Surgery, Razi Clinical Research Development Unit, Guilan University of Medical Sciences, Rasht, Iran.
- 3Department of Molecular Cell Biology, Faculty of Animal Science, Sari Agricultural Sciences and Natural Resources University, Sari, Iran.
- 4Medical Student, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
- 5Department of General Medicine, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
- 6Department of Biology, Division of Cell and Developmental Biology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran.
- 7Medical Laboratory Supervisor, Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Islamic Azad University, Tehran, Iran.
- 8I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia.
- 9Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
- 10Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- 11Department of Biology, Faculty of Basic Sciences, Imam Hossein Comprehensive University, Tehran, Iran.
Abstract
Ferroptosis, an iron-dependent form of regulated cell death characterized by the lethal accumulation of lipid peroxides, has emerged as a pivotal pathway in cancer biology and a promising therapeutic target. This review synthesizes the core molecular machinery governing ferroptosis, detailing the critical roles of iron metabolism through systems like transferrin/transferrin receptor 1 and ferritinophagy, the cystine/glutamate antiporter system (Xc⁻)/glutathione/GPX4 axis, and the recently discovered FSP1/CoQ10 pathway. We further explore the intricate interplay between lipid peroxidation, amino acid metabolism, and mitochondrial dysfunction, highlighting how their convergence dictates cellular susceptibility to ferroptotic death. The therapeutic potential of inducing ferroptosis in oncology is extensively reviewed, encompassing classic small-molecule inducers (e.g., erastin, RSL3, sorafenib) that target these key pathways. A significant focus is placed on the cutting-edge application of nanotechnology, discussing how various nanoparticles, including iron-based and organic systems, can potently induce ferroptosis through Fenton reactions, glutathione depletion, and targeted drug delivery, thereby overcoming traditional chemoresistance. We also introduce cold atmospheric plasma (CAP) as an emerging physical inducer of ferroptosis. Moreover, we examine the dynamic crosstalk between ferroptosis and the tumor immune microenvironment, particularly how CD8⁺ T cells and tumor-associated macrophages can modulate or respond to ferroptotic signals. Beyond summarizing the molecular basis of ferroptosis, this review critically integrates emerging advances in biomarker discovery, nanotechnology-enabled therapeutic strategies, and translational oncology to provide a clinically oriented perspective on ferroptosis-based cancer therapy. By highlighting biomarker-guided patient stratification, mechanisms of therapeutic resistance, and the principal challenges limiting clinical implementation, including tumor heterogeneity, off-target toxicity, pharmacokinetic constraints, and drug delivery barriers, this review provides a comprehensive framework for the rational development of precision oncology strategies targeting ferroptosis and identifies key priorities for future clinical translation.
Related
- Nano-formulations in therapeutic strategies targeting cancer ferroptosis
- Targeting the NLRP3 inflammasome in rheumatoid arthritis fibroblast-like synoviocytes: pathogenic mechanisms, therapeutic strategies, and translational perspectives
- Lactylation in liver fibrosis: from molecular mechanisms to targeted therapeutic strategies
- Molecular mechanisms for sustaining cancer stem cells characteristics and targeted therapeutic strategies
- Myocardial Ischemia-Reperfusion Injury: Molecular Mechanisms and Innovative Therapeutic Strategies
BibTeX
@article{khaledi2026targeting,
title = {{Targeting ferroptosis in cancer: molecular mechanisms and emerging therapeutic strategies.}},
author = {Mansoor Khaledi and Hasti Ahani and Faezeh Rezaei Tohid and Fatemeh Kazemi and Elham Amirkhani and Zeynab Daliri and Sahar Yadegari and Kosar Moarefvand and Behnam Poureslamfar and Fatemeh Sameni and Sajjad Yazdansetad},
journal = {Biochemistry and biophysics reports},
year = {2026},
month = oct,
doi = {10.1016/j.bbrep.2026.102825},
url = {https://europepmc.org/article/MED/42898245},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting ferroptosis in cancer: molecular mechanisms and emerging therapeutic strategies.
AU - Mansoor Khaledi
AU - Hasti Ahani
AU - Faezeh Rezaei Tohid
AU - Fatemeh Kazemi
AU - Elham Amirkhani
AU - Zeynab Daliri
AU - Sahar Yadegari
AU - Kosar Moarefvand
AU - Behnam Poureslamfar
AU - Fatemeh Sameni
AU - Sajjad Yazdansetad
PY - 2026
DA - 2026/10/09
JO - Biochemistry and biophysics reports
DO - 10.1016/j.bbrep.2026.102825
UR - https://europepmc.org/article/MED/42898245
AB - Ferroptosis, an iron-dependent form of regulated cell death characterized by the lethal accumulation of lipid peroxides, has emerged as a pivotal pathway in cancer biology and a promising therapeutic target. This review synthesizes the core molecular machinery governing ferroptosis, detailing the critical roles of iron metabolism through systems like transferrin/transferrin receptor 1 and ferritinophagy, the cystine/glutamate antiporter system (Xc⁻)/glutathione/GPX4 axis, and the recently discovered FSP1/CoQ10 pathway. We further explore the intricate interplay between lipid peroxidation, amino acid metabolism, and mitochondrial dysfunction, highlighting how their convergence dictates cellular susceptibility to ferroptotic death. The therapeutic potential of inducing ferroptosis in oncology is extensively reviewed, encompassing classic small-molecule inducers (e.g., erastin, RSL3, sorafenib) that target these key pathways. A significant focus is placed on the cutting-edge application of nanotechnology, discussing how various nanoparticles, including iron-based and organic systems, can potently induce ferroptosis through Fenton reactions, glutathione depletion, and targeted drug delivery, thereby overcoming traditional chemoresistance. We also introduce cold atmospheric plasma (CAP) as an emerging physical inducer of ferroptosis. Moreover, we examine the dynamic crosstalk between ferroptosis and the tumor immune microenvironment, particularly how CD8⁺ T cells and tumor-associated macrophages can modulate or respond to ferroptotic signals. Beyond summarizing the molecular basis of ferroptosis, this review critically integrates emerging advances in biomarker discovery, nanotechnology-enabled therapeutic strategies, and translational oncology to provide a clinically oriented perspective on ferroptosis-based cancer therapy. By highlighting biomarker-guided patient stratification, mechanisms of therapeutic resistance, and the principal challenges limiting clinical implementation, including tumor heterogeneity, off-target toxicity, pharmacokinetic constraints, and drug delivery barriers, this review provides a comprehensive framework for the rational development of precision oncology strategies targeting ferroptosis and identifies key priorities for future clinical translation.
SN - 2405-5808
ER -