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14.7
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Antioxidants
Special Issues
Lipid Peroxidation and Cancer
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Lipid Peroxidation and Cancer

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 6540

Special Issue Editors

Dr. Stefania Pizzimenti

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Guest Editor
Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy
Interests: lipid peroxidation; oxidative stress; cancer; chemoresistance; resistance to targeted therappies; melanoma; nanomedicine
Special Issues, Collections and Topics in MDPI journals
Dr. Giuliana Muzio

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Guest Editor
Department of Clinical and Biological Sciences, Universita degli Studi di Torino, 10124 Torino, Italy
Interests: tissue regenerations; biocompatibility and bioactivity of materials for medical devices; molecular aspects of osseointegration of dental implants; chemical and physical stimulation of implant integration; nanoparticles for theranostics in cancer; oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lipid metabolism reprogramming occurs during cancer development and progression and grants cancer cells a phenotype more favorable to proliferation and survival. Changes in fatty acid amount and profile affect several structural and biochemical characteristics of cancer cells. Alterations in the relative amounts of saturated, monounsaturated, and polyunsaturated fatty acids are known to vary the susceptibility of tumor cells to lipid peroxidation, to the effects of lipid peroxidation products and to lipid peroxidation-induced cell death indicated as ferroptosis.

In particular, the intracellular amount of polyunsaturated fatty acids (PUFAs), the lipid peroxidation substrates, their incorporation into the membrane phospholipids, and the antioxidant availability are key regulators of cancer cell proliferation/survival and of cancer progression, including the acquisition of resistance to antitumoral drugs. Moreover, the end products of lipid peroxidation, such as 4-hydroxynonenal (HNE) or malondialdehyde (MDA), have been reported to play a role in cancerogenesis and cancer progression.

All the above observations suggest that modulating lipid peroxidation in cancer is a promising approach for identifying new targetable molecular pathways.

This Special Issue aims to further deepen our understanding of the correlations among lipid peroxidation, cancer progression, and the onset of drug resistance, paving the way for the design of new therapeutic approaches. All types of "omics" investigations will contribute to attaining the principal aim of the Special Issue.

Original research articles, reviews, and clinical studies investigating the following aspects are welcome:

  1. Lipidomic characterization of lipid profiles specifically associated with the various types of cancer and with their progression;
  2. Correlation among the intracellular content of PUFA, susceptibility to lipid peroxidation, and proneness to ferroptosis in cancer cell lines and in vivo models;
  3. Deciphering the contribution of end-products of lipid peroxidation in the hallmarks of cancer;
  4. Evaluation of the possibility of modulating tumor progression by targeting lipid metabolism reprogramming and its consequences by new molecular or pharmacological strategies, including drug repurposing.

The Special Issue and the resulting discoveries may benefit from the involvement of researchers from various disciplines, from basic research to the clinical field.

Dr. Stefania Pizzimenti
Dr. Giuliana Muzio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lipid peroxidation
  • fatty acid metabolism
  • 4-hydroxynonenal (HNE)
  • malondialdehyde (MDA)
  • ferroptosis
  • carcinogenesis
  • cancer progression

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Published Papers (4 papers)

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Research

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19 pages, 1642 KB  
Article
Conjugated Linolenic Acids Induce Ferroptosis in Human and Zebrafish Melanoma Cells
by Zhuo Zhang, Alice Valembois, Caroline Rosier, Renaud Bonnevie, Ineke Neefs, Aurélien Warnant, Perrine Vermonden, Melissa M. Page, Olivier Feron, Cathy Debier and Yvan Larondelle
Antioxidants 2026, 15(3), 360; https://doi.org/10.3390/antiox15030360 - 12 Mar 2026
Viewed by 768
Abstract
Conjugated linolenic acids (CLnAs) are emerging as promising agents to trigger ferroptosis, a cell death driven by excessive lipid peroxidation, in cancer cells. Given the aggressive nature and treatment resistance of malignant melanoma, exploring CLnAs as therapeutic agents may offer a novel strategy [...] Read more.
Conjugated linolenic acids (CLnAs) are emerging as promising agents to trigger ferroptosis, a cell death driven by excessive lipid peroxidation, in cancer cells. Given the aggressive nature and treatment resistance of malignant melanoma, exploring CLnAs as therapeutic agents may offer a novel strategy to overcome these challenges. Here, we investigated the toxicity of four CLnA isomers on human (A375, WM266.4) and zebrafish (ZMEL1) melanoma cell lines. We observed a dose-dependent reduction in cell viability across all three tested cell lines. While human melanoma cells were more sensitive to CLnAs than ZMEL1 cells, treatment with ferroptosis inhibitors mitigated cell death in all models, confirming ferroptosis as the consistent primary mechanism of cell death. In addition, chemical inhibitors of ACSL4 and GPX4 modulated CLnA toxicity, further substantiating the ferroptotic mechanism by highlighting the role of these key regulators. Furthermore, fatty acid analysis revealed that CLnAs were effectively incorporated into phospholipids, generating substrates for lethal lipid peroxidation. At the transcriptional level, CLnA treatment significantly upregulated the pro-ferroptotic gene acsl4a in ZMEL1 cells. Overall, our study identifies specific CLnAs as potent ferroptosis inducers in both human and zebrafish melanoma cells and underscores the translational relevance of the zebrafish model based on a shared ferroptotic mechanism. Full article
(This article belongs to the Special Issue Lipid Peroxidation and Cancer)
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15 pages, 1835 KB  
Article
Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study
by Claudia R. Oliva, Susanne Flor and Corinne E. Griguer
Antioxidants 2026, 15(1), 40; https://doi.org/10.3390/antiox15010040 - 28 Dec 2025
Cited by 2 | Viewed by 920
Abstract
Ferroptosis is an iron-dependent, oxidative form of regulated cell death that has emerged as a therapeutic vulnerability in glioblastoma; however, the mitochondrial determinants that govern ferroptotic sensitivity remain poorly defined. Cytochrome c oxidase (CcO/Complex IV), a key regulator of mitochondrial respiration, contains two [...] Read more.
Ferroptosis is an iron-dependent, oxidative form of regulated cell death that has emerged as a therapeutic vulnerability in glioblastoma; however, the mitochondrial determinants that govern ferroptotic sensitivity remain poorly defined. Cytochrome c oxidase (CcO/Complex IV), a key regulator of mitochondrial respiration, contains two isoforms of subunit IV (COX4): COX4-1, a housekeeping isoform, and COX4-2, a stress-inducible variant. We previously found that COX4-1 expression protects glioma cells from erastin-induced ferroptosis, suggesting that mitochondria influence cell-death decisions independently of canonical ferroptotic regulators. Here, we used CRISPR-generated POLG-knockout ρ0 cells and transmitochondrial cybrids to isolate mitochondrial from nuclear contributions to ferroptosis sensitivity. Cybrids reconstituted with COX4-1-containing mitochondria restored CcO activity and recapitulated the ferroptosis-resistant phenotype, whereas COX4-2 cybrids remained insensitive to erastin. COX4-1 cybrids exhibited reduced labile iron, diminished cystine uptake, and low expression of SLC7A11 and GPX4, yet underwent apoptosis rather than ferroptosis upon erastin treatment. These findings demonstrate that mitochondrial COX4-1 rewires redox metabolism and diverts cell-death signaling away from ferroptosis toward apoptosis. Our results identify isoform-specific mitochondrial composition as a previously unrecognized determinant of regulated cell death and highlight COX4-1-driven mitochondrial remodeling as a potential mechanism of therapeutic resistance in glioblastoma. Full article
(This article belongs to the Special Issue Lipid Peroxidation and Cancer)
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21 pages, 3552 KB  
Article
Ferroptosis Enhances T Lymphocyte Infiltration into Glioblastoma Spheroids
by Anna Schwantes, Yara Shadid, Vanesa Maria Guerrero Ruiz, Blerina Aliraj, Anja Wickert, Megan A. Palmer, Sofie P. Meyer, Andreas Weigert, Bernhard Brüne and Dominik C. Fuhrmann
Antioxidants 2025, 14(11), 1373; https://doi.org/10.3390/antiox14111373 - 19 Nov 2025
Cited by 2 | Viewed by 1574
Abstract
Glioblastoma is one of the most aggressive and therapeutically challenging brain tumors. It is characterized by a highly immunosuppressive tumor microenvironment and poor prognosis, requiring novel treatment strategies. Along this line, ferroptosis has been proposed. To study the impact of ferroptosis on glioblastoma [...] Read more.
Glioblastoma is one of the most aggressive and therapeutically challenging brain tumors. It is characterized by a highly immunosuppressive tumor microenvironment and poor prognosis, requiring novel treatment strategies. Along this line, ferroptosis has been proposed. To study the impact of ferroptosis on glioblastoma cells and immune cell infiltration, we established a spheroid model using LN229 glioblastoma cells and verified ferroptosis by measuring lipid peroxidation and RNA expression of ferroptosis-related genes. We then co-cultured spheroids with human peripheral blood mononuclear cells to follow the infiltration of distinct immune cell subsets by flow cytometry and immunohistochemistry. T lymphocyte infiltration into ferroptotic spheroids compared to control spheroids became apparent with the notion that ferroptotic cells attracted T cells more efficiently compared to apoptotic or necrotic cells. Mechanistically, ferroptotic glioblastoma spheroids released high amounts of ATP, which caused T cell attraction, while ATP deprivation reduced this effect. Ferroptosis appears to be an interesting therapy approach but might need co-treatments to ensure proper T cell activation. Full article
(This article belongs to the Special Issue Lipid Peroxidation and Cancer)
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Review

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38 pages, 1997 KB  
Review
The Redox–Adhesion–Exosome (RAX) Hub in Cancer: Lipid Peroxidation-Driven EMT Plasticity and Ferroptosis Defense with HNE/MDA Signaling and Lipidomic Perspectives
by Moon Nyeo Park, Jinwon Choi, Rosy Iara Maciel de Azambuja Ribeiro, Domenico V. Delfino, Seong-Gyu Ko and Bonglee Kim
Antioxidants 2025, 14(12), 1474; https://doi.org/10.3390/antiox14121474 - 8 Dec 2025
Cited by 12 | Viewed by 2567
Abstract
Cancer cell plasticity drives metastasis and therapy resistance through dynamic transitions between epithelial, mesenchymal, and neural crest stem-like (NCSC) states; however, a unifying mechanism that stabilizes these transitions remains undefined. To address this gap, we introduce a N-cadherin (CDH2)-centered redox–adhesion–exosome (RAX) hub that [...] Read more.
Cancer cell plasticity drives metastasis and therapy resistance through dynamic transitions between epithelial, mesenchymal, and neural crest stem-like (NCSC) states; however, a unifying mechanism that stabilizes these transitions remains undefined. To address this gap, we introduce a N-cadherin (CDH2)-centered redox–adhesion–exosome (RAX) hub that links oxidative signaling, adhesion dynamics, and exosome-mediated immune communication into a closed-loop framework. Within this network, reactive oxygen species (ROS) pulses license epithelial–mesenchymal transition (EMT), AXL–FAK/Src signaling consolidates mesenchymal adhesion, and selective exosomal cargoes—including miR-21, miR-200, miR-210, and PD-L1—propagate plasticity and immune evasion. Lipid peroxidation acts as a central checkpoint connecting ROS metabolism to PUFA membrane remodeling and ferroptosis vulnerability, buffered by NRF2–GPX4 and FSP1/DHODH axes, thereby converting transient oxidative pulses into persistent malignant states. Mechanistically, the RAX hub synthesizes findings from EMT/CSC biology, ferroptosis defenses, and exosome research into a self-reinforcing system that sustains tumor heterogeneity and stress resilience. Evidence from single-cell and spatial transcriptomics, intravital ROS imaging, and exosome cargo-selector studies supports the feasibility of this model. We further outline validation strategies employing HyPer–EMT–CDH2 tri-reporters, CRISPR perturbation of YBX1/ALIX cargo selectors, and spatial multi-omics in EMT-high tumors. Clinically, tumors enriched in EMT/NCSC programs—such as melanoma, neuroblastoma, small-cell lung cancer, pancreatic ductal adenocarcinoma, and triple-negative breast cancer (TNBC)—represent RAX-dependent contexts. These insights highlight biomarker-guided opportunities to target adhesion switches, ferroptosis defenses, and exosome biogenesis through lipid peroxidation-centered strategies using liquid-biopsy panels (exosomal CDH2, miR-200, miR-210) combined with organoid and xenograft models. By linking lipid peroxidation to ferroptosis defense and oxidative stress adaptation, the RAX hub aligns with the thematic focus of lipid metabolism and redox control in cancer progression. Collectively, the RAX framework may provide a conceptual basis for precision oncology by reframing metastasis and therapy resistance as emergent network properties. Full article
(This article belongs to the Special Issue Lipid Peroxidation and Cancer)
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