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Ferroptosis, ROS and Cell Death Cytomodulator Compounds

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

Deadline for manuscript submissions: 31 October 2026 | Viewed by 5958

Special Issue Editor


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Guest Editor
Department of Dental and Biomedical Materials Science, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8588, Japan
Interests: ferroptosis; ROS; cytomodulator compounds biomaterials; cell responses; bone formation

Special Issue Information

Dear Colleagues,

Aim: To discuss the potential of cytomodulator compounds in controlling the roles of ferroptosis and ROS in regulated cell death within disease and bone formation contexts.

Scope: Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). Unlike apoptosis or necrosis, ferroptosis is characterized by overwhelming oxidative stress and damage to membrane lipids, ultimately compromising cell integrity. ROS, which are chemically reactive molecules derived from oxygen, play a central role in initiating and propagating ferroptosis by promoting lipid peroxidation and disrupting redox homeostasis.

To regulate ferroptosis and ROS-induced cell death, cytomodulator compounds have emerged as promising tools. These molecules can either induce or inhibit ferroptosis by modulating cellular antioxidant defenses, iron metabolism, and lipid peroxidation pathways. For instance, ferroptosis inhibitors like ferrostatin-1 and liproxstatin-1 function as radical-trapping agents, neutralizing ROS and preventing lipid peroxidation. Conversely, inducers such as erastin and RSL3 impair glutathione metabolism or inhibit GPX4, enhancing ROS accumulation and triggering ferroptotic death.

These cytomodulators are being explored as potential therapeutic inhibitors to protect healthy tissues from oxidative damage and as inducers to selectively kill cancer cells. Thus, targeting ROS and ferroptosis with cytomodulator compounds offers a powerful strategy to manipulate cell death pathways in various diseases.

Dr. Alireza Valanezhad
Guest Editor

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Keywords

  • cell death
  • ferroptosis
  • ROS
  • GPX4
  • lipid peroxidation
  • inhibitors
  • inducers
  • cytomodulator compounds
  • cancer
  • disease
  • bone formation

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Published Papers (3 papers)

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Research

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15 pages, 15798 KB  
Article
Targeting Ferroptosis to Restore Salivary Gland Homeostasis in an Obesity Model
by Gi Cheol Park, Hanaro Park, Soo-Young Bang, Ji Min Kim, Sung-Chan Shin, Yong-il Cheon, Ha-Nee Kwon, Jung Hwan Cho and Byung-Joo Lee
Int. J. Mol. Sci. 2026, 27(1), 514; https://doi.org/10.3390/ijms27010514 - 4 Jan 2026
Viewed by 799
Abstract
Obesity is a systemic metabolic disorder that is known to impair various organ systems; however, its precise impact on salivary gland homeostasis remains unclear. Recent studies have implicated ferroptosis—an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress—in glandular [...] Read more.
Obesity is a systemic metabolic disorder that is known to impair various organ systems; however, its precise impact on salivary gland homeostasis remains unclear. Recent studies have implicated ferroptosis—an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress—in glandular dysfunction. In this study, we used leptin-deficient (ob/ob) mice to elucidate the role of ferroptosis in obesity-associated salivary gland pathology. The protective effects of ferroptosis inhibition were evaluated by administering ferrostatin-1 (a lipid reactive oxygen species [ROS] scavenger) and deferoxamine (an iron chelator) for an 8-week period. Obese mice exhibited significantly increased body weight, food intake, and hyperglycemia. These systemic changes are accompanied by profound histological alterations in the salivary glands, including lipid droplet accumulation, acinar atrophy, and mitochondrial ultrastructural damage. These alterations correlate with the hallmarks of ferroptotic injury, including increased ROS levels (p < 0.001), elevated malondialdehyde levels (p < 0.01), suppressed glutathione peroxidase 4 activity (p < 0.01), and iron overload (p < 0.001). Salivary gland fibrosis, inflammation, and secretory dysfunction were evident, characterized by the upregulation of TGF-β (p < 0.01) and Collagen I (p < 0.05), reduced expression of aquaporin-5 and amylase, and dysregulated levels of autophagy-related markers (LC3B and p62). Treatment with either ferrostatin-1 or deferoxamine significantly mitigated these pathologies; however, the degree of efficacy varied depending on the specific parameters that were examined. Thus, our findings implicate ferroptosis as a critical contributor to salivary gland dysfunction in obesity and suggest that pharmacological inhibition of this pathway represents a viable therapeutic strategy for preserving glandular integrity under metabolic stress. Full article
(This article belongs to the Special Issue Ferroptosis, ROS and Cell Death Cytomodulator Compounds)
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14 pages, 4719 KB  
Article
Ferroptosis Inhibition Enhances Osteoblast Activity: The Role of Liproxstatin-1 and Coenzyme Q10
by Alireza Valanezhad, Tetsurou Odatsu, Farzaneh Valanezhad, Shigeaki Abe and Ikuya Watanabe
Int. J. Mol. Sci. 2025, 26(24), 12059; https://doi.org/10.3390/ijms262412059 - 15 Dec 2025
Viewed by 1206
Abstract
Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, is implicated in various degenerative diseases and bone regeneration. In this study, we hypothesized that the ferroptosis inhibitors Liproxstatin-1 (Lip-1) and Coenzyme Q10 (CoQ10) play a dual role in protecting cells against [...] Read more.
Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, is implicated in various degenerative diseases and bone regeneration. In this study, we hypothesized that the ferroptosis inhibitors Liproxstatin-1 (Lip-1) and Coenzyme Q10 (CoQ10) play a dual role in protecting cells against ferroptotic damage and promoting osteogenic differentiation in MC3T3-E1 cells. Erastin-induced ferroptosis significantly reduced cell viability and increased lipid peroxidation, as evidenced by BODIPY™ 581/591 C11 staining. Both Lip-1 and CoQ10 decreased lipid peroxidation and restored cell viability, particularly at early treatment points. Post-treatment recovery experiments showed that both agents reversed erastin-induced damage, with Lip-1 having a stronger and more sustained effect. ALP activity assays on day 14 revealed dose-dependent increases with Lip-1 and moderate stimulation with CoQ10, indicating additional osteoinductive properties. Moreover, cell density affected sensitivity to lipid peroxidation, with higher cell densities providing protection through antioxidant pooling. These results highlight CoQ10 and Lip-1 as promising candidates for bone tissue engineering, as they offer protection against ferroptosis and promote osteoblast differentiation. Overall, this study emphasizes the therapeutic potential of ferroptosis modulators for bone regeneration. Full article
(This article belongs to the Special Issue Ferroptosis, ROS and Cell Death Cytomodulator Compounds)
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Review

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22 pages, 2355 KB  
Review
Ferroptosis in Autoimmune Diseases: Research Advances and Therapeutic Strategies
by Ziman He, Bo Liu, Zuquan Xian, Aimin Gong and Xiaokang Jia
Int. J. Mol. Sci. 2025, 26(21), 10449; https://doi.org/10.3390/ijms262110449 - 28 Oct 2025
Cited by 4 | Viewed by 3522
Abstract
Ferroptosis, an iron-dependent programmed cell death driven by lipid peroxidation, plays a critical role in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. This review systematically explores the interaction between ferroptosis and the immune system, highlighting its dynamic regulation of [...] Read more.
Ferroptosis, an iron-dependent programmed cell death driven by lipid peroxidation, plays a critical role in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. This review systematically explores the interaction between ferroptosis and the immune system, highlighting its dynamic regulation of immune cell function (e.g., Treg cell stability, neutrophil activity) and inflammatory microenvironments via signaling pathways including JAK/STAT and NF-κB. Ferroptosis suppresses inflammation in rheumatoid arthritis by eliminating pro-inflammatory synoviocytes but exacerbates tissue damage in systemic lupus erythematosus through neutrophil ferroptosis. While ferroptosis inhibitors (e.g., Fer-1) and inducers (e.g., IKE) show promise in preclinical models, clinical translation faces challenges such as disease-specific mechanistic heterogeneity, insufficient drug selectivity, and complex metabolic interactions. Future research should integrate multi-omics, organoid models, and AI-driven predictions to develop precision-targeted strategies, offering novel therapeutic paradigms for autoimmune diseases. Full article
(This article belongs to the Special Issue Ferroptosis, ROS and Cell Death Cytomodulator Compounds)
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