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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 12858

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Dr. Sara Cruciani

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Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
Interests: stem cell biology; cell differentiation; cellular mechanisms; cell senescence; stress response; gene and protein expression
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Dear Colleagues,

Oxidative stress plays a pivotal role in regulating cellular aging and the functional decline of stem cells. Reactive oxygen species (ROS), produced as by-products of cellular metabolism, can damage DNA, proteins, and lipids, thereby triggering senescence—a state of irreversible cell cycle arrest. In stem cells, a tightly controlled redox balance is essential for preserving their self-renewal and differentiation capacities. Excessive oxidative stress disrupts this balance, leading to premature senescence and loss of regenerative potential. Moreover, the accumulation of senescent cells in tissues contributes to aging and age-related diseases through the senescence-associated secretory phenotype (SASP), which promotes chronic inflammation and alters tissue microenvironments. Understanding the interplay between oxidative stress, cellular senescence, and stem cell biology is crucial for developing therapeutic strategies aimed at enhancing tissue regeneration and counteracting degenerative disorders.

We invite you to submit original studies, reviews, and perspectives that explore the role of oxidative stress and cellular senescence in stem cell biology and regenerative medicine. Contributions that deepen our understanding of redox regulation, senescence-associated mechanisms, and their impacts on stem cell function and tissue regeneration are especially welcome.

We look forward to receiving your contribution.

Dr. Sara Cruciani
Guest Editor

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Keywords

stem cells
cell senescence
regenerative medicine
antioxidant strategies
age-related diseases

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Published Papers (7 papers)

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Research

Jump to: Review

13 pages, 654 KB

Open AccessArticle

Integrative Analysis of 4-Hydroxynonenal-Modified Proteins and Plasma Metabolome in Breast Cancer Patients

by Morana Jaganjac, Matea Nikolac Perkovic, Tea Horvat, David Rojo, Marija Krizic, Natalija Dedic Plavetic, Damir Vrbanec, Biserka Orehovec, Kamelija Zarkovic and Neven Zarkovic

Antioxidants 2026, 15(2), 265; https://doi.org/10.3390/antiox15020265 - 21 Feb 2026

Cited by 1 | Viewed by 483

Abstract

Breast cancer is a highly heterogeneous malignancy, characterized by diverse genetic, epigenetic, and phenotypic variations, as well as by metabolic reprogramming and oxidative stress. Lipid peroxidation bioactive product 4-hydroxynonenal (4-HNE) plays a significant role in the development and progression of cancer. In this study, we quantified circulating 4-HNE-modified proteins and performed comprehensive untargeted metabolomic profiling of the patients’ plasma using LC-ESI-QTOF-MS and GC-EI-QMS, aiming to investigate systemic metabolic pathways associated with oxidative damage in breast cancer. Significantly elevated levels of 4-HNE-modified proteins were detected in breast cancer patients compared to healthy controls, accompanied by distinct metabolomic signatures enriched in lipid metabolism. Several metabolites, including specific long-chain fatty acids, exhibited significant correlations with circulating 4-HNE-modified proteins, suggesting an interaction between lipid peroxidation-driven protein modification and breast cancer-associated metabolic reprogramming. Overall, this study provides evidence of associations between systemic 4-HNE-mediated protein modification and altered metabolic profiles in breast cancer, highlighting oxidative stress–related metabolites as potential biomarkers and pointing to redox-metabolic crosstalk in breast cancer patients. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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19 pages, 1940 KB

Open AccessArticle

Protective Effect of Multifloral Honey on Stem Cell Aging in a Dynamic Cell Culture Model

by Fikriye Fulya Kavak, Sara Cruciani, Giuseppe Garroni, Diletta Serra, Rosanna Satta, Ibrahim Pirim, Melek Pehlivan and Margherita Maioli

Antioxidants 2026, 15(1), 115; https://doi.org/10.3390/antiox15010115 - 16 Jan 2026

Cited by 1 | Viewed by 875

Abstract

Natural compounds, as honey-derived flavonoids and phenolic compounds, are increasingly investigated for their potential to mitigate skin aging and prevent oxidative stress-induced cellular damages. In this context, a dynamic cell culture model was employed to assess the protective influence of honey pre-treatment on stem cell–associated genes and the Wingless-related integration site (Wnt) signaling pathway following ultraviolet (UV)-induced aging. Using a bioreactor, skin stem cells (SSCs) derived from healthy skin biopsies and human skin fibroblasts (HFF1) were pre-treated with 1% honey for 48 h and then exposed to UV. Real-time quantitative polymerase chain reaction (RT-qPCR) analyses were performed on Wnt signaling and anti-aging molecular responses. Honey pre-treatment enhanced the expression of pluripotency markers (Octamer-binding transcription factor 4 (Oct4); SRY-box transcription factor 2 (Sox2)) and reduced senescence-related cell cycle regulators (cyclin-dependent kinase inhibitor 2A (p16); cyclin-dependent kinase inhibitor 1A (p21); tumor protein 53 (p53)) in SSCs. In UV-damaged SSCs, honey also significantly increased Wnt3a expression. In fibroblasts, honey pre-treatment upregulated Heat shock protein 70 (Hsp70) and Hyaluronan synthase 2 (HAS2) expression, while downregulating caspase-8 (CASP8), indicating a protective role against UV-mediated cellular stress. We also analyzed nitric oxide release and the total antioxidant capacity of cells after treatment. Collectively, these findings suggest that honey may safeguard skin stem cells from UV-induced aging by modulating pluripotency and senescence-associated genes and regulating differentiation through alterations in Wnt signaling. Furthermore, Hsp70 upregulation in fibroblasts appears to strengthen cellular stress responses and support homeostatic stability. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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25 pages, 31724 KB

Open AccessArticle

Oxidative Stress and PRKN-Mediated Senescence Link RhoA/ROCK Signaling to Epithelial Remodeling in Allergic Rhinitis

by Xuan Yuan, Wei Zhong, Shaobing Xie, Liyuan Liu, Wenjing Gu, Yixiang Zeng, Hua Zhang, Weihong Jiang, Zhihai Xie and Peisong Gao

Antioxidants 2026, 15(1), 77; https://doi.org/10.3390/antiox15010077 - 7 Jan 2026

Viewed by 853

Abstract

Allergic rhinitis (AR) is characterized by persistent epithelial remodeling, yet the upstream drivers and molecular mechanisms remain poorly defined. Analysis of nasal mucosa from AR patients revealed marked epithelial remodeling, oxidative stress, and Th2 inflammation. Transcriptome analysis of nasal mucosa revealed RhoA as one of the most upregulated genes, with expression positively correlating with disease severity. Using epithelial-specific RhoA-deficient mice (RhoA^cKO) and fasudil, a RhoA/ROCK inhibitor, we found that loss of RhoA/ROCK signaling markedly attenuated nasal Th2 inflammation, oxidative stress, and epithelial remodeling following allergen challenge. Further transcriptome analysis demonstrated that elevated RhoA activation was associated with increased epithelial cellular senescence. Both in vitro and in vivo studies confirmed that epithelial RhoA activation promotes allergen- or Th2 cytokine-induced cellular senescence, whereas genetic or pharmacologic elimination of senescent cells alleviated allergic inflammation and tissue remodeling. Pathway analysis identified PRKN (parkin) as a central node within RhoA-regulated, senescence-associated networks in AR. Functional studies showed that PRKN overexpression mitigated IL-13-induced mitochondrial dysfunction, oxidative stress, and epithelial senescence in human nasal epithelial cells. Together, these findings reveal that RhoA-driven epithelial senescence contributes to allergic inflammation and epithelial remodeling in AR and identify PRKN as a potential therapeutic target to restore epithelial homeostasis. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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24 pages, 11297 KB

Open AccessArticle

Epithelial AhR Suppresses Allergen-Induced Oxidative Stress and Senescence via c-Myc Regulation

by Zhifeng Chen, Wenjing Gu, Rongjun Wan, Yixiang Zeng, Xudong Xiang, Ruoyun Ouyang and Peisong Gao

Antioxidants 2026, 15(1), 22; https://doi.org/10.3390/antiox15010022 - 23 Dec 2025

Viewed by 894

Abstract

Environmental allergens trigger epithelial reactive oxygen species (ROS) production and cellular senescence, contributing to airway inflammation. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor responsive to environmental stimuli, may modulate this process. Single-cell transcriptomics from allergen-challenged bronchoalveolar brushings of allergic asthma and non-asthmatic allergic control subjects were analyzed for ROS, senescence, and AhR activity. Club cell-specific p16 knockout (p16^ΔScgb1a1) and AhR-deficient (AhR^ΔScgb1a1) mice were used to assess epithelial senescence and AhR function. Single-cell analysis revealed epithelial senescence as a hallmark of allergen-induced asthma. p16^ΔScgb1a1 mice exhibited reduced ROS levels and airway inflammation. Single-cell analysis also demonstrated increased AhR activity and ROS generation in airway epithelial cells of allergen-treated asthmatics, and ROS correlated positively with AhR activity and senescence. It was documented that the regulation of AhR on senescence was attenuated by VAF347, whereas AhR deficiency exacerbated ROS generation and inflammation in AhR^ΔScgb1a1 mice. RNA-seq identified senescence as a key AhR-regulated pathway, implicating c-Myc, TGF-β2, and SERPINE1 as major targets. AhR binding to the c-Myc promoter was confirmed by ChIP-PCR, and pharmacologic inhibition of c-Myc with EN4 reduced allergen-induced ROS, senescence, and inflammation. These findings demonstrate that epithelial AhR suppresses allergen-induced ROS generation and cellular senescence via direct regulation of c-Myc. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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22 pages, 5849 KB

Open AccessArticle

Hyperosmolarity-Induced Oxidative Stress Leads to Senescence in Human Corneal Epithelial Cells (HCEPC) via DNA Damage, Metabolic Disturbance and Mitophagy Decline

by Yongjie Zhang and Tingjun Fan

Antioxidants 2025, 14(11), 1381; https://doi.org/10.3390/antiox14111381 - 19 Nov 2025

Viewed by 1423

Abstract

Background: Dry eye disease (DED), characterized by tear film hyperosmolarity, can lead to corneal epithelial damage. The mechanisms linking hyperosmotic stress to human corneal epithelial cell (HCEPC) damage are not fully understood. Methods: A DED model was established by exposing HCEPCs to sustained hyperosmotic stress (400 mOsm/L) over multiple passages in vitro. Senescence was assessed using senescence-associated-β-galactosidase (SA-β-gal) staining, 5-ethynyl-2′-deoxyuridine (EdU) assays, p16^INK4A and senescence-associated secretory phenotypes (SASP) analysis. Mechanisms were investigated by measuring reactive oxygen species (ROS), mitochondrial function, energy metabolism, DNA damage, and inflammatory signaling. The role of autophagy was probed pharmacologically. Results: Hyperosmotic stress induced HCEPC senescence, driven by mitochondrial dysfunction, oxidative stress, DNA damage, bioenergetic crisis, and compromised autophagy (especially mitophagy). Autophagy and mitophagy play a key role in regulating senescence progression. Enhancing autophagy with LYN-1604 ameliorated oxidative stress, improved energy homeostasis, and attenuated senescence. Inhibiting autophagy exacerbated these states. Conclusion: Hyperosmolarity promotes HCEPC senescence via mitochondrial dysfunction and oxidative damage. Autophagy serves a critical protective role, and its enhancement represents a promising therapeutic strategy for DED. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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Review

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31 pages, 3483 KB

Open AccessReview

Reactive Oxygen and Nitrogen Species on Monocyte and Macrophage Biology

by Francisco Rafael Jimenez-Trinidad, Sofia Morini, Armanda Buffon, Andrea de Prisco, Greta Galati, Astrid de Ciutiis, Alessia d’Aiello, Francesc Jiménez-Altayó, Ana Paula Dantas, Giovanna Liuzzo and Anna Severino

Antioxidants 2026, 15(3), 389; https://doi.org/10.3390/antiox15030389 - 19 Mar 2026

Viewed by 897

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are central regulators of monocyte and macrophage biology, shaping their survival, differentiation, migration, and effector functions. In monocytes and macrophages, ROS and RNS arise from endogenous sources, such as mitochondria, NADPH oxidases, and myeloperoxidase, and from exogenous stimuli including pathogens, damaged tissues, and environmental oxidants. These reactive intermediates converge on redox-sensitive pathways such as NF-κB, Nrf2/HO-1, mitochondrial ROS signalling, and the NLRP3 inflammasome, thereby integrating metabolic stress with inflammatory activation. Redox balance is a key determinant of macrophage polarization: heightened ROS and RNS production drives pro-inflammatory M1 programs, whereas tightly regulated oxidative signalling supports M2 phenotypes associated with tissue repair and resolution. In chronic inflammatory disorders, notably atherosclerosis, oxidative stress amplifies monocyte recruitment, foam-cell formation, plaque instability, and maladaptive immunometabolic responses. The aim of this review is to recapitulate the major sources and functions of ROS and RNS in monocytes and macrophages and to synthesize current evidence on how these pathways collectively maintain or disrupt immune homeostasis. We further highlight emerging therapeutic strategies, such as NOX inhibitors, mitochondrial-targeted antioxidants, and Nrf2 activators, that seek to restore redox balance and offer promising avenues for the treatment of cardiovascular and immune-mediated diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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39 pages, 4384 KB

Open AccessReview

Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons

by Bojan Stojanovic, Ivan Jovanovic, Milica Dimitrijevic Stojanovic, Bojana S. Stojanovic, Vojin Kovacevic, Ivan Radosavljevic, Danijela Jovanovic, Marina Miletic Kovacevic, Nenad Zornic, Ana Azanjac Arsic, Stevan Eric, Nikola Mirkovic, Jelena Nesic, Stefan Jakovljevic, Snezana Lazarevic, Ivana Milivojcevic Bevc and Bojan Milosevic

Antioxidants 2025, 14(8), 987; https://doi.org/10.3390/antiox14080987 - 12 Aug 2025

Cited by 35 | Viewed by 6694

Abstract

Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology—providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype. Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation. This review explores the intricate interplay between redox imbalance and cellular senescence, emphasizing mitochondrial dysfunction, SASP dynamics, and their implications in aging and cancer. We discuss current senotherapeutic strategies—including senolytics, senomorphics, antioxidants, gene therapy, and immunotherapy—that aim to eliminate or modulate senescent cells to restore tissue homeostasis. Understanding the heterogeneity and context-specific behavior of senescent cells remains crucial for optimizing these therapies. Future research should focus on addressing key knowledge gaps, including the standardization of senescence biomarkers such as circulating miRNAs, refinement of predictive preclinical models, and development of composite clinical endpoints. These efforts are essential to translate mechanistic insights into effective senotherapeutic interventions and enable the safe integration of senescence-targeting strategies into routine clinical practice. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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