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Antioxidants
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Antioxidants and Oxidative Stress at the Crossroads of Autophagy and...
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Antioxidants and Oxidative Stress at the Crossroads of Autophagy and Ferroptosis

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 November 2026 | Viewed by 4948

Special Issue Editors

Dr. Elzbieta Janda

E-Mail Website
Guest Editor
Health Sciences Department, Magna Graecia University, Catanzaro, Italy
Interests: toxicology; quinone oxidoreductase; polyphenols; autophagy; energy metaboilism; hepatic steatosis
Special Issues, Collections and Topics in MDPI journals
Dr. Flavia Biamonte

E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, Magna Græcia University of Catanzaro, Catanzaro, Italy
Interests: iron metabolism; mitochondria bioenergetics; ferroptosis; cancer; cancer therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress plays a pivotal role as both a trigger of ferroptosis and a central regulator of autophagy. Both processes can be finely tuned by natural and synthetic antioxidants, which exert dual and context-dependent effects. For instance, polyphenols and other bioactive compounds may either promote or inhibit autophagy and ferroptosis depending on their concentration, the cellular redox state, and the specific tissue or tumor microenvironment. By influencing iron metabolism, glutathione balance, lipid peroxidation, and reactive oxygen species (ROS) signaling, they act at the crossroads of these two pathways. This ability enables them to either protect normal cells from oxidative injury or, conversely, sensitize tumor cells to ferroptosis and/or autophagy through interconnected mechanisms.

This Special Issue welcomes both original research and comprehensive reviews exploring the biological activities of natural and synthetic antioxidants, with particular attention to the molecular mechanisms underlying their regulation of oxidative stress, ferroptosis, and autophagy. Priority will be given to contributions that identify direct molecular targets of antioxidants and clarify how they influence the delicate balance between cytoprotection and cell death with translational and therapeutic implications. However, high-quality manuscripts addressing any aspect of these processes will also be considered.

Dr. Elzbieta Janda
Dr. Flavia Biamonte
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

  • antioxidants
  • oxidative stress
  • ferroptosis
  • autophagy
  • molecular mechanisms

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Published Papers (4 papers)

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Research

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24 pages, 4993 KB  
Article
The RAGE–Ferroptosis Axis Drives Oxidative Stress-Associated Inflammatory Lung Injury in Viral Infection
by Wenhui Guo, Junhao Luo, Siyu Pu, Simin Cui, Haijun Zhu, Peiqing He and Rongbao Gao
Antioxidants 2026, 15(4), 434; https://doi.org/10.3390/antiox15040434 - 31 Mar 2026
Viewed by 793
Abstract
The receptor for advanced glycation end-products (RAGE) is a lung-enriched pattern recognition receptor implicated in inflammatory responses. Its role in ferroptosis-mediated lung injury during viral infection, however, remains unclear. Here, we combined bioinformatics analysis with in vitro and in vivo experimental validation to [...] Read more.
The receptor for advanced glycation end-products (RAGE) is a lung-enriched pattern recognition receptor implicated in inflammatory responses. Its role in ferroptosis-mediated lung injury during viral infection, however, remains unclear. Here, we combined bioinformatics analysis with in vitro and in vivo experimental validation to investigate the RAGE–ferroptosis axis in influenza virus infection. Cross-analysis of RAGE- and ferroptosis-related genes identified overlapping candidates, suggesting functional crosstalk. Influenza-infected A549 cells exhibited ferroptotic cell death, characterized by Fe2+ accumulation, reactive oxygen species (ROS) elevation, and lipid peroxidation, which was markedly attenuated by the RAGE inhibitor FPS-ZM1. In A/PR/8/34 (H1N1)-infected female C57BL/6J mice, FPS-ZM1 treatment improved survival, reduced lung injury, restored redox balance, and modulated key ferroptosis regulators ACSL4, POR, and GPX4. Moreover, RAGE inhibition decreased M1 macrophage and neutrophil infiltration and reduced pro-inflammatory cytokines. Collectively, these findings reveal that RAGE activation drives ferroptosis and amplifies oxidative stress–associated lung injury, whereas RAGE inhibition mitigates tissue damage via the ACSL4/POR/GPX4 pathway and immunomodulation. This study identifies the RAGE–ferroptosis axis as a potential therapeutic target for severe pulmonary inflammation. Full article
(This article belongs to the Special Issue Antioxidants and Oxidative Stress at the Crossroads of Autophagy and Ferroptosis)
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26 pages, 18198 KB  
Article
L-Selenomethionine Alleviates Cryo-Induced Ferroptosis Through the NRF2–SLC7A11–GPX4 Pathway, Improving Post-Thaw In Vitro Quality of Dairy Goat Spermatozoa
by Zi-Tao Jiang, Shun-Kai Yang, Xu-Dong Zhou, Xu Zhang, Zi-Tong Hu, Song-Mao Guo, Guo-Yu Zhang, Shuai-Qi Han, Fei Wen, Xiao-Xu Chen and Jian-Hong Hu
Antioxidants 2026, 15(3), 392; https://doi.org/10.3390/antiox15030392 - 20 Mar 2026
Viewed by 964
Abstract
Background: Cryopreservation induces oxidative stress, membrane disruption, and mitochondrial injury in spermatozoa, leading to impaired motility and fertility. Selenium, as an essential trace element, protects cells from oxidative damage through selenoproteins such as glutathione peroxidase 4 (GPX4), a critical enzyme that detoxifies lipid [...] Read more.
Background: Cryopreservation induces oxidative stress, membrane disruption, and mitochondrial injury in spermatozoa, leading to impaired motility and fertility. Selenium, as an essential trace element, protects cells from oxidative damage through selenoproteins such as glutathione peroxidase 4 (GPX4), a critical enzyme that detoxifies lipid hydroperoxides and inhibits ferroptosis. This study investigated whether supplementation with L-selenomethionine (L-SeMet), an organic selenium source with superior bioavailability and lower toxicity than inorganic forms, could alleviate cryo-induced sperm injury by suppressing ferroptosis. Methods & Results: Dairy goat sperm were cryopreserved with 0, 2, 4, 6, 8, 10 μM L-SeMet. Supplementation with 6 μM L-SeMet significantly improved motility, membrane and acrosome integrity, and mitochondrial membrane potential. Biochemical assays showed reduced iron, ROS, and MDA levels, alongside increased ATP, SOD, and GSH contents. Proteomic analysis identified 148 differentially expressed proteins, including up-regulation of GPX4, FTH1, VDAC2, and VDAC3—core ferroptosis regulators. Metabolomic profiling further revealed enrichment in unsaturated fatty acid biosynthesis, amino acid metabolism, and the TCA cycle, pathways closely linked to ferroptosis regulation. Transmission electron microscopy confirmed that L-SeMet preserved mitochondrial ultrastructure. Mechanistically, L-SeMet mirrored the ferroptosis inhibitor N-acetyl-L-cysteine and reversed RSL3-induced oxidative damage. Western blotting verified activation of the NRF2–SLC7A11–GPX4 antioxidant axis and inhibition of KEAP1 expression. Conclusions: Collectively, these findings demonstrate that L-SeMet protects spermatozoa from cryo-induced injury by stabilizing redox homeostasis, maintaining mitochondrial function, and inhibiting ferroptosis. The results highlight ferroptosis as a critical mechanism of sperm cryodamage and identify L-SeMet as a promising metabolic intervention to enhance post-thaw sperm quality and fertility. Full article
(This article belongs to the Special Issue Antioxidants and Oxidative Stress at the Crossroads of Autophagy and Ferroptosis)
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Review

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20 pages, 2168 KB  
Review
Interaction of Ferroptosis and Immune-Mediated Inflammation in Psoriasis
by Emanuele Giorgio, Cristiana Galeano, Giuseppe Natali, Lavinia Petriaggi, Maria Concetta Faniello, Elzbieta Janda, Francesco Saverio Costanzo, Anna Martina Battaglia and Flavia Biamonte
Antioxidants 2026, 15(3), 382; https://doi.org/10.3390/antiox15030382 - 18 Mar 2026
Viewed by 903
Abstract
Psoriasis is classically defined as an immune-mediated disease. However, many patients do not achieve durable remission after immune-targeted therapies, suggesting that further pathogenic mechanisms may contribute to the persistence of psoriasis. Here, we propose ferroptosis, an iron-dependent regulated cell death driven by lipid [...] Read more.
Psoriasis is classically defined as an immune-mediated disease. However, many patients do not achieve durable remission after immune-targeted therapies, suggesting that further pathogenic mechanisms may contribute to the persistence of psoriasis. Here, we propose ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation and failure of lipid repair, as a potential link between metabolic stress and immune-mediated inflammation in psoriasis. We summarize experimental evidence showing that membrane lipids remodeling, antioxidant suppression, lipid peroxidation, and dysregulated iron handling together define ferroptosis-permissive niches within psoriatic lesions. We also discuss functional studies demonstrating that ferroptosis modulation can reshape psoriasiform inflammation and explore how ferroptotic stress may amplify inflammatory signaling at the immune-epidermal interface, reinforcing IL-17/TNF/IFN-γ pathways. Finally, we discuss ferroptosis-related transcriptomic signatures as a potential approach to stratify psoriasis, capturing metabolic features that are not reflected by cytokine profiling. The translational opportunities and constraints for ferroptosis-targeted interventions are outlined, highlighting epidermal redox homeostasis as a new therapeutic frontier in psoriasis. Full article
(This article belongs to the Special Issue Antioxidants and Oxidative Stress at the Crossroads of Autophagy and Ferroptosis)
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24 pages, 3292 KB  
Review
Redox Network Dysfunction: Integrating Ferroptosis and Cuproptosis Across Human Diseases
by Federica Li Pomi, Guglielmo Di Leo, Sara Genovese, Francesco Borgia and Sebastiano Gangemi
Antioxidants 2026, 15(1), 24; https://doi.org/10.3390/antiox15010024 - 23 Dec 2025
Cited by 5 | Viewed by 1738
Abstract
Oxidative stress (OS) is increasingly recognized as a dynamic disturbance of cellular redox networks rather than a simple imbalance between oxidants and antioxidants. In this context, ferroptosis and cuproptosis—two regulated and metal-dependent forms of cell death—emerge as key mechanisms linking OS to metabolic [...] Read more.
Oxidative stress (OS) is increasingly recognized as a dynamic disturbance of cellular redox networks rather than a simple imbalance between oxidants and antioxidants. In this context, ferroptosis and cuproptosis—two regulated and metal-dependent forms of cell death—emerge as key mechanisms linking OS to metabolic dysfunction, inflammation, and tissue injury. This review integrates findings from biochemical, lipidomic and metallomic studies to describe how lipid peroxidation (LPO), glutathione (GSH)–Glutathione Peroxidase 4 (GPX4) activity, ferritinophagy, copper-induced mitochondrial protein lipoylation, and altered communication between organelles generate distinct redox signatures across diseases. By examining cutaneous, metabolic, cardiovascular, infectious, neurodegenerative, and oncologic conditions, we outline the shared redox pathways that connect iron- and copper-dependent cell death to systemic inflammation, immune dysregulation, and chronic tissue damage. Common oxidative markers—such as oxidized phospholipids, lipid aldehydes including 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA), and systemic metal imbalance—are highlighted as potential indicators of disease severity and as emerging therapeutic targets. We also discuss innovative analytical tools, including redox lipidomics, metallomic profiling and artificial-intelligence (AI)-based classification approaches, which improve the characterization of redox vulnerability and may guide the development of precision redox therapies. Overall, ferroptosis and cuproptosis represent unifying mechanisms that connect OS to multisystem disease and provide new opportunities for diagnostic refinement and targeted antioxidant-based interventions. Full article
(This article belongs to the Special Issue Antioxidants and Oxidative Stress at the Crossroads of Autophagy and Ferroptosis)
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