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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: 31 May 2026 | Viewed by 11890

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Special Issue Editor

Dr. Miquel Mulero

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Guest Editor

1. Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain
2. Center of Environmental, Food and Toxicological Technology‐TecnATox, Rovira i Virgili University, 43201 Reus, Spain
Interests: natural products; polyphenols; nutrition; metabolic syndrome; obesity; biomarkers; inflammation; insulin resistance; ER stress; autophagy; NAFLD; circadian rhythms; microbiota; ROS; apoptosis

Special Issue Information

Dear Colleagues,

The Special Issue "Oxidative Stress in Hepatic Diseases" focuses on the pivotal role of oxidative stress in the progression and pathology of various liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, viral hepatitis, and liver fibrosis. Oxidative stress results from an imbalance between the production of reactive oxygen species (ROS) and the liver's antioxidant defense systems, leading to cellular damage and inflammatory responses that drive liver disease progression. This issue aims to explore the mechanisms through which oxidative stress impacts hepatic health, including mitochondrial dysfunction, lipid peroxidation, and inflammatory cascades. We invite research on the molecular pathways involved, the identification of novel biomarkers for early diagnosis, and potential therapeutic strategies targeting oxidative stress. Through both original research and review articles, this Special Issue seeks to provide insights into innovative approaches to reduce oxidative damage, improve liver function, and ultimately enhance patient outcomes in hepatic disease management.

Dr. Miquel Mulero
Guest Editor

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Keywords

oxidative stress
hepatic diseases
liver fibrosis
reactive oxygen species (ROS)
mitochondrial dysfunction
lipid peroxidation
antioxidant defense
non-alcoholic fatty liver disease (NAFLD)
alcoholic liver disease
hepatoprotective strategies

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Published Papers (7 papers)

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Research

Jump to: Review, Other

28 pages, 11173 KB

Open AccessArticle

Natural Extracts of Alnus japonica Induce BAK-Dependent Autophagy to Inhibit Liver Cancer Stem Cell Tumorigenesis

by Kenly Wuputra, Yoshimasa Matsuura, Satoshi Gushiken, Hirosuke Fukuda, Ya-Han Yang, Chia-Chen Ku, Chun-Chieh Wu, Ying-Chu Lin, Yi-Chun Tsai, Deng-Chyang Wu, Toshihiko Nozaki, Kohsuke Kato, Atsushi Kawaguchi, Kyosuke Nagata, Yoshiharu Tanaka and Kazunari K. Yokoyama

Antioxidants 2026, 15(6), 685; https://doi.org/10.3390/antiox15060685 (registering DOI) - 29 May 2026

Abstract

Background: Cancer stem cells (CSCs) contribute to hepatocellular carcinoma (HCC) progression and therapeutic resistance. Natural products with antioxidant and bioactive properties may offer novel strategies to suppress CSC-driven tumorigenesis. Methods: We investigated the effects of unfermented and fermented Alnus japonica bark extracts on CSC-like rG2-DC-1C cells. Cell proliferation, invasion, and xenograft tumor formation were assessed, and autophagy/apoptosis markers were analyzed. Results: Bark extracts reduced OCT4 expression, suppressed CSC proliferation and invasion, and inhibited xenograft tumor formation. Mechanistically, extracts activated BAK-dependent autophagy, evidenced by LC3B accumulation and p62 modulation, whereas diarylheptanoids Hirsutenone (Hir) and Oregonin (Ore) primarily induced apoptosis via Caspase-3 cleavage. Blocking autophagy with chloroquine or BAK knockdown reversed the anti-invasive effects of bark extracts, confirming BAK’s role in CSC suppression. Component analysis suggests quercetin contributes to autophagy induction, though synergistic effects of other constituents remain possible. Conclusions: Together, these findings indicate that Alnus japonica bark extracts suppress CSC-driven liver tumorigenesis through autophagy, while Hir and Ore act via apoptosis, highlighting complementary mechanisms that broaden the therapeutic potential of this traditional medicinal plant and support further preclinical validation. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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15 pages, 13547 KB

Open AccessArticle

Protective Effects of Vitis coignetiae Vine Stem Extract Against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

by Nam-Kyu Yoon, Jeongjun Lee, Hunsuk Chung, Jae-Kwang Kim and Sae-Kwang Ku

Antioxidants 2026, 15(5), 651; https://doi.org/10.3390/antiox15050651 - 21 May 2026

Viewed by 244

Abstract

Vitis coignetiae Pulliat ex Planch, commonly referred to as “meoru” in Korea (crimson glory vine), is a grape species belonging to the Vitaceae family, native to East Asia. This study investigated the protective effects of a hot water extract prepared from the vine stems of V. coignetiae (CG) in a model of CCl₄-induced acute liver injury. Mice received oral administration of CG (100, 200, and 400 mg/kg) or silymarin (200 mg/kg) once daily for 7 consecutive days, followed by intraperitoneal injection of CCl₄ (0.5 mL/kg). CG attenuated CCl₄-induced oxidative stress, as indicated by reduced hepatic malondialdehyde production and decreased 4-hydroxynonenal-positive cells. These effects were accompanied by restoration of antioxidant defense systems, including increased glutathione levels and superoxide dismutase and catalase activities, along with increased nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression. Hepatic inflammatory responses were also attenuated by CG treatment, with reductions in TNF-α, interleukin (IL)-1β, and IL-6 levels, inflammatory cell infiltration, and nuclear factor-κB (NF-κB) mRNA expression. Furthermore, CG attenuated apoptotic cell death, as evidenced by decreased cleaved caspase-3-positive and cleaved poly(ADP-ribose) polymerase (PARP)-positive cells. CG also lowered serum aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase levels, and alleviated hepatocellular degeneration in histopathological analysis. Collectively, these findings suggest that CG may exert protective effects against CCl₄-induced liver injury by regulating oxidative stress, inflammation, and apoptosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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17 pages, 3780 KB

Open AccessArticle

Selenomethionine Counteracts T-2 Toxin-Induced Liver Injury by Mitigating Oxidative Stress Damage Through the Enhancement of Antioxidant Enzymes

by Yan Wang, Mingxia Zhou, Suisui Gao, Pishun Li, Xiaofeng Zheng, Di Tu and Lingchen Yang

Antioxidants 2025, 14(7), 866; https://doi.org/10.3390/antiox14070866 - 15 Jul 2025

Cited by 4 | Viewed by 1361

Abstract

T-2 toxin, a highly toxic feed contaminant, poses a significant health risk to both humans and animals, particularly targeting the liver. This study aimed to investigate the protective effects and underlying mechanisms of selenomethionine (SeMet) against T-2-induced liver injury in mice. We pretreated mice with SeMet before exposing them to an acute liver injury model induced by T-2. By assessing indicators related to liver injury, oxidative stress, inflammatory response, and mitochondrial disorder, we found that SeMet mitigated T-2-induced liver damage. Specifically, SeMet upregulated the gene expression and activity of antioxidant enzymes like glutathione peroxidase 1 (GPX1), which consequently reduced reactive oxygen species (ROS), inflammatory cytokines levels, and normalized mitochondrial biogenesis. Conclusively, SeMet effectively alleviated T-2-induced mitochondrial overproduction, inflammatory responses, and oxidative stress damage in hepatocyte primarily by enhancing GPX1 and other antioxidant enzymes, thereby exerting a protective effect on the liver. This study provides theoretical and experimental support for further research and application of SeMet in the livestock industry. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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25 pages, 6489 KB

Open AccessArticle

The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity

by Thu-Hang Thi Nghiem, Kim Anh Nguyen, Fedho Kusuma, Soyoung Park, Jeongmin Park, Yeonsoo Joe, Jaeseok Han and Hun Taeg Chung

Antioxidants 2025, 14(3), 307; https://doi.org/10.3390/antiox14030307 - 3 Mar 2025

Cited by 15 | Viewed by 6379

Abstract

Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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Review

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23 pages, 1310 KB

Open AccessReview

Therapeutic Potential of Cytoglobin and Neuroglobin in Oxidative Stress-Driven Liver Diseases

by Le Thi Thanh Thuy, Hoang Hai, Pham Tuan Anh, Nguyen Bui Tam Chi, Tran Van Bao, Tran Dang Anh Huyen, Nguyen Tran Quang Sang and Michelle L. Hermiston

Antioxidants 2026, 15(4), 485; https://doi.org/10.3390/antiox15040485 - 14 Apr 2026

Viewed by 684

Abstract

Chronic liver diseases, including fibrosis and hepatocellular carcinoma (HCC), are primarily driven by oxidative stress, yet traditional antioxidant therapies often lack the specificity and efficacy required for clinical success. This review evaluates the emerging therapeutic potential of two atypical globins, cytoglobin (CYGB) and neuroglobin (NGB), exploring their unique hexacoordinated heme structures that enable potent reactive oxygen and nitrogen species (ROS/RNS) scavenging and redox-regulated signaling. We summarize a broad range of in vitro and in vivo evidence demonstrating that these globins deactivate hepatic stellate cells, reduce extracellular matrix accumulation, and function as tumor suppressors by modulating pathways such as Raf/MEK/ERK and NRF2. In human cohorts, CYGB expression levels inversely correlate with the progression of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and HCC, highlighting its potential as a clinical biomarker. Furthermore, recombinant protein therapies involving CYGB and NGB show promise in promoting collagen degradation and inhibiting malignant transformation. We conclude that CYGB and NGB represent sophisticated catalytic redox regulators that offer a novel therapeutic paradigm for restoring redox homeostasis. While delivery and pharmacokinetic barriers remain, these globins are highly promising candidates for first-in-class biologics in hepatology. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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30 pages, 3084 KB

Open AccessReview

Antioxidants Acteoside and Orientin as Emerging Agents in Synergistic Cancer Therapy: A Focus on Innovative Applications

by Jagoda Szkudlarek, Ludwika Piwowarczyk and Anna Jelińska

Antioxidants 2025, 14(7), 855; https://doi.org/10.3390/antiox14070855 - 12 Jul 2025

Cited by 2 | Viewed by 2291

Abstract

Cancers, particularly those resistant to treatment, stand as one of the most significant challenges in medicine. Frequently, available therapies need to be improved, underscoring the necessity for innovative treatment modalities. Over the years, there has been a resurgence of interest in natural plant substances, which have been traditionally overlooked as anticancer agents. A prime example of this is natural antioxidants, such as acteoside (ACT) and orientin (ORI), which offer novel approaches to cancer treatment, emphasizing liver cancer compared to other cancer types. They reduce oxidative stress by activating the Nrf2/ARE pathway and exhibit anticancer activity, e.g., decreasing Bcl-2 and Bcl-XL expression and increasing Bax levels. This review explores the individual effects of ACT and ORI and their synergistic interactions with sorafenib, temozolomide, 5-fluorouracil (for ACT), celecoxib, and curcumin (for ORI), highlighting their enhanced anticancer efficacy. In addition, ACT and ORI successfully integrate into various drug delivery systems (DDSs), including metal-containing carriers such as nanoparticles (NPs), nanoshells (NSs), quantum dots (QDs), and liposomes as representative examples of lipid-based drug delivery systems (LBDDSs). Advanced methods, including nanotechnology, offer potential solutions to low bioavailability, paving the way for the use of these substances in anticancer therapy. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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Other

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21 pages, 1326 KB

Open AccessSystematic Review

Inflammatory Adipokines and Potential Oxidative Stress-Related Mechanisms Linking MASLD with Subclinical Atherosclerosis Within CKM Syndrome: A Systematic Review and Meta-Analysis

by Cezara-Andreea Gerdanovics, Șoimița-Mihaela Suciu, Olga-Hilda Orășan, Ioana Para, Vladiana-Romina Turi, Adela-Sitar Tăut, Mircea-Vasile Milaciu, Mirela-Georgiana Perne, Teodora-Gabriela Alexescu, Lorena Ciumărnean, Alexandru Gerdanovics, Vlad-Dumitru Brata and Angela Cozma

Antioxidants 2026, 15(6), 684; https://doi.org/10.3390/antiox15060684 (registering DOI) - 29 May 2026

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder linked to cardio-kidney–metabolic (CKM) syndrome, early vascular injury and redox imbalance. Inflammatory adipokines such as retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) may contribute to this hepatic–vascular interplay by integrating metabolic inflammation, oxidative stress and endothelial dysfunction. Therefore, the present study aimed to investigate the contribution of the inflammatory adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) to the hepatic–vascular interplay in MASLD within the cardio-kidney–metabolic (CKM) syndrome. Materials and Methods: We performed a systematic review and meta-analysis of studies evaluating circulating RBP4 and LCN2 levels in MASLD. PubMed, Scopus, and Web of Science were searched. Twenty studies were included in the qualitative synthesis, and ten in the quantitative meta-analysis. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Vascular findings were synthesized narratively because of heterogeneity in outcomes. Results: Circulating RBP4 levels were significantly higher in MASLD patients than in controls (SMD = 0.64, 95% CI: 0.08 to 1.20, p = 0.026; I² = 91.2%). LCN2 levels were also significantly elevated (SMD = 1.92, 95% CI: 0.83 to 3.00, p < 0.001; I² = 98.0%). Compared with RBP4, LCN2 showed a larger pooled effect size, although heterogeneity remained very high. In the qualitative synthesis, adipokines, particularly LCN2, were associated with markers of vascular injury, including carotid intima–media thickness, plaque burden, arterial stiffness, endothelial dysfunction, coronary severity, and cardiovascular events. Conclusions: Both RBP4 and LCN2 were elevated in MASLD, supporting a link between adipokine dysregulation and hepatic metabolic dysfunction within the broader cardio-kidney–metabolic (CKM) syndrome. LCN2 appeared to better reflect the inflammatory, metabolic, and vascular burden of disease. These findings support the view of MASLD as a systemic disorder within the CKM syndrome and highlight the potential of inflammatory adipokines as non-invasive biomarkers of integrated hepatic, metabolic, and vascular dysfunction. Full article

(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)

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