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Regulation and Targeting of Ferroptosis in Tumor and Beyond (Second Edition)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 6140

Special Issue Editor

Dr. Yong Teng

E-Mail Website
Guest Editor
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
Interests: metastasis; molecular pathway; cancer models; metabolism; tumor microenvironment; drug screening and development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ferroptosis is a newly emerged programmed necrosis process implicated in multiple biological and pathological conditions. As a novel form of regulated cell death (RCD), ferroptosis has garnered increasing attention in studies on numerous human diseases in the last decade. Numerous cellular factors and potential regulatory pathways underlying ferroptosis have been elucidated; however, its precise mechanism and function are not well understood. Emerging evidence has demonstrated that ferroptosis is an iron-dependent form of nonapoptotic cell death induced by excessive lipid peroxidation, which is accompanied by an increased uptake of polyunsaturated fatty acids into the cellular membrane and further unfolding an ancient vulnerability in multiple contexts. Ferroptosis susceptibility has been demonstrated in many cancers, including hepatocellular carcinoma, breast cancer, and head and neck cancer. Ferroptosis induction, a nonapoptotic, regulated cell death modality, is a promising anti-cancer strategy.

The main aim of this topic is to study the mechanistic underpinnings of ferroptosis. Those include how ferroptosis is regulated at the molecular level and how to target its pathways therapeutically. Here, we will pay extra attention to these articles about novel/non-canonical ferroptosis pathways. This SI aims to advance our understanding of the fundamental biological process of ferroptosis and potentially identify new approaches to manipulate it for therapeutic benefits. Original research articles, reviews, and mini-reviews are welcome to be submitted to this research topic. Papers are expected to cover but are not limited to the following topics:

  1. Basic mechanisms involved in ferroptosis and critical regulators of ferroptosis.
  2. The role of proto-oncogenes and tumor suppressor genes in canonical and non-canonical ferroptosis regulation.
  3. Targeting ferroptosis for disease treatment.
  4. Ferroptosis and immunotherapy.
  5. Ferroptosis and cellular metabolism.
  6. Studies related to other cell death mechanisms (including but not limited to pyroptosis, apoptosis, necroptosis, and PANoptosis).
  7. The role of ferroptosis in drug resistance and stem cells.
  8. New drugs and targeting therapeutics associated with ferroptosis.

Dr. Yong Teng
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • ferroptosis
  • iron
  • tumor survival and cell death
  • oxidation
  • drug development
  • anti-cancer strategies

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Published Papers (3 papers)

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Research

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17 pages, 1880 KB  
Article
Characterization of Differential GPX4 Essentiality Between Intrahepatic and Extrahepatic Cholangiocarcinoma via Leveraging of a Large-Scale Functional Genomic Screen
by Ye Rim Lee, Chaeyoung Seo, Md Abdullah, Su Hyun Baek and Seung Jin Lee
Int. J. Mol. Sci. 2025, 26(24), 11990; https://doi.org/10.3390/ijms262411990 - 12 Dec 2025
Viewed by 652
Abstract
Ferroptosis has emerged as a promising therapeutic vulnerability of diverse malignancies, yet the regulatory circuits adopted by each in cholangiocarcinoma (CCA) subtypes remain incompletely understood. We integrated the genome-wide CRISPR–Cas9 loss-of-function screens and transcriptomic profiles of the Cancer Dependency Map and then systematically [...] Read more.
Ferroptosis has emerged as a promising therapeutic vulnerability of diverse malignancies, yet the regulatory circuits adopted by each in cholangiocarcinoma (CCA) subtypes remain incompletely understood. We integrated the genome-wide CRISPR–Cas9 loss-of-function screens and transcriptomic profiles of the Cancer Dependency Map and then systematically assessed the essentiality of ferroptosis suppressor genes (FSGs) in the intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. Nineteen and 16 essential FSGs were identified in iCCA and eCCA, respectively, among which GPX4 exhibited a significantly higher dependency in iCCA. Pharmacological inhibition of GPX4 with RSL3 markedly reduced cell viability and induced lipid peroxidation in iCCA cell lines, whereas eCCA cell lines displayed pronounced resistance associated with elevated GPX4 expression. A transcriptomic comparison revealed enrichment of WNT signaling in eCCA. Co-treatment with the tankyrase inhibitor XAV-939 and RSL3 enhanced growth inhibition of eCCA cells, indicating that WNT signaling contributed to ferroptosis resistance. These findings indicate that iCCA exhibits a preferential dependency on GPX4, whereas WNT–β-catenin signaling mediates resistance in eCCA. Collectively, the results clarify the molecular basis of subtype-specific ferroptosis vulnerability and offer a rationale for combinatorial therapeutic strategies that integrate GPX4 and WNT pathway inhibition when treating refractory eCCA. Full article
(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond (Second Edition))
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Review

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28 pages, 1093 KB  
Review
Targeting Ferroptosis in Nasopharyngeal Carcinoma: Mechanisms, Resistance, and Precision Therapeutic Opportunities
by Jaewang Lee and Jong-Lyel Roh
Int. J. Mol. Sci. 2025, 26(23), 11439; https://doi.org/10.3390/ijms262311439 - 26 Nov 2025
Viewed by 1465
Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck malignancy strongly associated with Epstein–Barr virus (EBV) infection and characterized by high radiosensitivity but frequent therapy resistance. Despite advances in radiotherapy, chemotherapy, and immunotherapy, relapse and metastasis remain major challenges, underscoring the need for novel [...] Read more.
Nasopharyngeal carcinoma (NPC) is a head and neck malignancy strongly associated with Epstein–Barr virus (EBV) infection and characterized by high radiosensitivity but frequent therapy resistance. Despite advances in radiotherapy, chemotherapy, and immunotherapy, relapse and metastasis remain major challenges, underscoring the need for novel therapeutic approaches. This review aims to provide an integrated overview of the molecular mechanisms governing ferroptosis in NPC and to clarify how these pathways contribute to therapy resistance while revealing potential therapeutic vulnerabilities. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising target in NPC. Core regulators include the system xCT–GSH–GPX4 antioxidant axis, iron metabolism, and lipid remodeling enzymes such as ACSL4, with epigenetic modifiers (METTL3, IGF2BP2, HOXA9) and EBV-driven signaling further shaping ferroptosis responses. EBV-driven oncogenic programs substantially reshape ferroptosis sensitivity in NPC by activating the Nrf2/Keap1 antioxidant axis, stabilizing SLC7A11 and GPX4, and modulating iron and redox metabolism. These viral mechanisms suppress ferroptotic stress and contribute to both radioresistance and chemoresistance. Suppression of ferroptosis underlies both radioresistance and chemoresistance, whereas restoration of ferroptosis re-sensitizes tumors to treatment. Natural compounds including solasodine, berberine, cucurbitacin B, and celastrol-curcumin combinations, as well as pharmacologic modulators such as HO-1 inhibitors and GPX4 antagonists, have shown ferroptosis-inducing effects in preclinical models, although their translational potential remains to be clarified. Nanotechnology-based platforms (e.g., Bi2Se3 nanosheet hydrogels) further enhance efficacy and reduce toxicity by enabling controlled drug delivery. Biomarker discovery, encompassing ferroptosis-related gene signatures, epigenetic regulators, immune infiltration patterns, EBV DNA load, and on-treatment redox metabolites, provides a foundation for patient stratification. Integration of ferroptosis modulation with radiotherapy, chemotherapy, and immunotherapy represents a compelling strategy to overcome therapy resistance. In synthesizing these findings, this review highlights both the mechanistic basis and the translational promise of ferroptosis modulation as a strategy to overcome treatment resistance in NPC. Future directions include biomarker validation, optimization of drug delivery, early-phase clinical trial development, and multidisciplinary collaboration to balance ferroptosis induction in tumors while protecting normal tissues. Collectively, ferroptosis is emerging as both a vulnerability and a therapeutic opportunity for improving outcomes in NPC. Full article
(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond (Second Edition))
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27 pages, 1248 KB  
Review
Metabolic Regulation of Ferroptosis in Breast Cancer
by Natalija Glibetic and Michael Weichhaus
Int. J. Mol. Sci. 2025, 26(19), 9686; https://doi.org/10.3390/ijms26199686 - 4 Oct 2025
Cited by 2 | Viewed by 3668
Abstract
Breast cancer, a leading global malignancy, exhibits extensive metabolic reprogramming that drives tumorigenesis, therapy resistance, and survival. Ferroptosis, an iron-dependent regulated cell death mechanism characterized by lipid peroxidation, emerges as a promising therapeutic vulnerability, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). [...] Read more.
Breast cancer, a leading global malignancy, exhibits extensive metabolic reprogramming that drives tumorigenesis, therapy resistance, and survival. Ferroptosis, an iron-dependent regulated cell death mechanism characterized by lipid peroxidation, emerges as a promising therapeutic vulnerability, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This literature review comprehensively explores the metabolic regulation of ferroptosis in breast cancer cells, focusing on how dysregulated pathways modulate sensitivity or resistance. The review will discuss iron homeostasis, including upregulated transferrin receptor 1 (TFR1), diminished ferroportin, mitochondrial dynamics, and ferritinophagy, which catalyze ROS via Fenton reactions. It will examine glutathione (GSH) metabolism through the GPX4-GSH axis, with subtype-specific reliance on cystine import via xCT or de novo cysteine synthesis. Lipid metabolism will be analyzed as the core battleground, highlighting polyunsaturated fatty acid (PUFA) incorporation by ACSL4 promoting peroxidation, contrasted with monounsaturated fatty acid (MUFA) protection via SCD1, alongside subtype adaptations. Further, the review will address tumor microenvironment influences, such as cysteine supply from cancer-associated fibroblasts and oleic acid from adipocytes. Oncogenic signaling (e.g., RAS, mTOR) and tumor suppressors (e.g., p53) will be evaluated for their roles in resistance or sensitivity. Intersections with glucose metabolism (Warburg effect) and selenium-dependent antioxidants will be explored. Therapeutically, the review will consider targeting these nodes with GPX4 inhibitors or iron overload, synergized with immunotherapy for immunogenic cell death. Future directions will emphasize multi-omics integration and patient-derived organoids to uncover subtype-specific strategies for precision medicine in breast cancer. Full article
(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond (Second Edition))
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