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Keywords = ferroptosis-related gene

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27 pages, 1619 KiB  
Review
Epigenetic Mechanisms Governing Nrf2 Expression and Its Role in Ferroptosis
by Linbo Li, Xinjun Liu, Zizhen Si and Xidi Wang
Biomedicines 2025, 13(8), 1913; https://doi.org/10.3390/biomedicines13081913 - 5 Aug 2025
Abstract
Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation participating in various diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular redox homeostasis and a key determinant of ferroptosis resistance. Nrf2 activates [...] Read more.
Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation participating in various diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular redox homeostasis and a key determinant of ferroptosis resistance. Nrf2 activates the expression of downstream antioxidant genes to protect cells from oxidative stress and ferroptosis. Consequently, precise regulation of Nrf2 expression is crucial. Recent studies have revealed that complex epigenetic mechanisms involving DNA methylation, histone modifications, and non-coding RNA networks regulate Nrf2 expression. DNA methylation usually suppresses while histone acetylation promotes Nrf2 expression. The influences of histone methylation on NFE2L2 are site- and methylation degree-dependent. m6A modification stabilizes NFE2L2 mRNA to promote Nrf2 expression and thereby inhibit ferroptosis. This article summarizes current understanding of the epigenetic mechanisms controlling Nrf2 expression and Nrf2-mediated ferroptosis pathways and their implications in disease models. The challenges associated with the epigenetic regulation of Nrf2 and future research directions are also discussed. A comprehensive understanding of this regulatory interplay could open new avenues for intervention in ferroptosis-related diseases by fine-tuning cellular redox balance through the epigenetic modulation of Nrf2. Full article
(This article belongs to the Special Issue Oxidative Stress in Health and Disease)
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20 pages, 1376 KiB  
Review
Molecular Mechanisms of Cadmium-Induced Toxicity and Its Modification
by Jin-Yong Lee, Maki Tokumoto and Masahiko Satoh
Int. J. Mol. Sci. 2025, 26(15), 7515; https://doi.org/10.3390/ijms26157515 - 4 Aug 2025
Viewed by 220
Abstract
Cadmium (Cd) is a toxic environmental heavy metal that exerts harmful effects on multiple tissues, including the kidney, liver, lung, and bone, and is also associated with the development of anemia. However, the precise molecular mechanisms underlying Cd-induced toxicity remain incompletely understood. In [...] Read more.
Cadmium (Cd) is a toxic environmental heavy metal that exerts harmful effects on multiple tissues, including the kidney, liver, lung, and bone, and is also associated with the development of anemia. However, the precise molecular mechanisms underlying Cd-induced toxicity remain incompletely understood. In this paper, we review the recent molecular mechanisms of Cd-induced toxicity and its modification, with a particular emphasis on our recent findings. Using a combination of DNA microarray analysis, protein–DNA binding assays, and siRNA-mediated gene silencing, we identified several transcription factors, YY1, FOXF1, ARNT, and MEF2A, as novel molecular targets of Cd. The downregulation of their downstream genes, including UBE2D2, UBE2D4, BIRC3, and SLC2A4, was directly associated with the expression of cytotoxicity. In addition, PPARδ plays a pivotal role in modulating cellular susceptibility to Cd-induced renal toxicity, potentially by regulating apoptosis-related signaling pathways. In addition to apoptosis pathways, Cd toxicity through ROS generation, ferroptosis and pyroptosis were summarized. Furthermore, it has been revealed that Cd suppresses the expression of iron transport-related genes in duodenal epithelial cells leading to impaired intestinal iron absorption as well as decreased hepatic iron levels. These findings provide a mechanistic basis for Cd-induced iron deficiency anemia, implicating disrupted iron homeostasis as a contributing factor. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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21 pages, 7017 KiB  
Article
Chronic Heat Stress Caused Lipid Metabolism Disorder and Tissue Injury in the Liver of Huso dauricus via Oxidative-Stress-Mediated Ferroptosis
by Yining Zhang, Yutao Li, Ruoyu Wang, Sihan Wang, Bo Sun, Dingchen Cao, Zhipeng Sun, Weihua Lv, Bo Ma and Ying Zhang
Antioxidants 2025, 14(8), 926; https://doi.org/10.3390/antiox14080926 - 29 Jul 2025
Viewed by 218
Abstract
High-temperature stress has become an important factor that has restricted the aquaculture industry. Huso dauricus is a high-economic-value fish that has faced the threat of thermal stress. Based on this point, our investigation aimed to explore the detailed mechanism of the negative impacts [...] Read more.
High-temperature stress has become an important factor that has restricted the aquaculture industry. Huso dauricus is a high-economic-value fish that has faced the threat of thermal stress. Based on this point, our investigation aimed to explore the detailed mechanism of the negative impacts of heat stress on the liver metabolism functions in Huso dauricus. In this study, we set one control group (19 °C) and four high-temperature treatment groups (22 °C, 25 °C, 28 °C, 31 °C) with 40 fish in each group for continuous 53-day heat exposure. Histological analysis, biochemical detection, and transcriptome technology were used to explore the effects of heat stress on the liver structure and functions of juvenile Huso dauricus. It suggested heat-stress-induced obvious liver injury and reactive oxygen species accumulation in Huso dauricus with a time/temperature-dependent manner. Serum total protein, transaminase, and alkaline phosphatase activities showed significant changes under heat stress (p < 0.05). In addition, 6433 differentially expressed genes (DEGs) were identified based on the RNA-seq project. Gene Ontology enrichment analysis showed that various DEGs could be mapped to the lipid-metabolism-related terms. KEGG enrichment and immunohistochemistry analysis showed that ferroptosis and FoxO signaling pathways were significantly enriched (p < 0.05). These results demonstrated that thermal stress induced oxidative stress damage in the liver of juvenile Huso dauricus, which triggered lipid metabolism disorder and hepatocyte ferroptosis to disrupt normal liver functions. In conclusion, chronic thermal stress can cause antioxidant capacity imbalance in the liver of Huso dauricus to mediate the ferroptosis process, which would finally disturb the lipid metabolism homeostasis. In further research, it will be necessary to verify the detailed cellular signaling pathways that are involved in the heat-stress-induced liver function disorder response based on the in vitro experiment, while the multi-organ crosswalk mode under the thermal stress status is also essential for understanding the comprehensive mechanism of heat-stress-mediated negative effects on fish species. Full article
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18 pages, 5443 KiB  
Article
Toosendanin Induces Hepatotoxicity by Facilitating ALOX5-Mediated Lipid Peroxidation and Sensitizing Cells to Ferroptosis
by Jiajie Ni, Liru Huang, Yifan Tian, Changxin Zhao, Ziyi Zhou, Feihai Shen and Zhiying Huang
Pharmaceuticals 2025, 18(7), 1078; https://doi.org/10.3390/ph18071078 - 21 Jul 2025
Viewed by 257
Abstract
Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying [...] Read more.
Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis. Full article
(This article belongs to the Section Pharmacology)
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12 pages, 3941 KiB  
Article
Integrated Metabolomic and Transcriptomic Analysis Reveals the Regulatory Effects of Curcumin on Bovine Ovarian Granulosa Cells
by Bingfei Zhang, Le Chen, Liping Mei, Xianbo Jia, Shiyi Chen, Jie Wang, Hengwei Yu, Songjia Lai and Wenqiang Sun
Int. J. Mol. Sci. 2025, 26(14), 6713; https://doi.org/10.3390/ijms26146713 - 12 Jul 2025
Viewed by 430
Abstract
Curcumin is a natural polyphenolic compound known to alleviate follicular developmental abnormalities associated with ovarian dysfunction. However, its precise molecular mechanisms remain to be fully elucidated. In this study, we systematically investigated the regulatory effects of curcumin on bovine ovarian granulosa cells through [...] Read more.
Curcumin is a natural polyphenolic compound known to alleviate follicular developmental abnormalities associated with ovarian dysfunction. However, its precise molecular mechanisms remain to be fully elucidated. In this study, we systematically investigated the regulatory effects of curcumin on bovine ovarian granulosa cells through integrated transcriptomic and metabolomic analyses. A total of 503 and 200 significantly altered metabolites were identified in the positive and negative ion modes, respectively, with enrichment in key pathways such as glutathione metabolism, fatty acid biosynthesis, and the phosphatidylinositol signaling pathway. Transcriptomic profiling revealed 1168 differentially expressed genes (582 upregulated and 586 downregulated) which were significantly enriched in pathways related to glutathione metabolism and cellular senescence. Joint multi-omics analysis further demonstrated that curcumin significantly influenced pathways related to glutathione metabolism, cysteine, and methionine metabolism, as well as multiple forms of programmed cell death, including apoptosis, necroptosis, and ferroptosis. Collectively, these findings suggest that curcumin may enhance the antioxidant capacity and survival of granulosa cells by maintaining redox homeostasis and modulating cell fate. This work provides new insights into the potential cellular mechanisms underlying the protective effects of curcumin on granulosa cell function. Full article
(This article belongs to the Section Molecular Biology)
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37 pages, 974 KiB  
Review
The Molecular Interplay Between p53-Mediated Ferroptosis and Non-Coding RNAs in Cancer
by Carolina Punziano, Silvia Trombetti, Michela Grosso, Maria Lina Tornesello and Raffaella Faraonio
Int. J. Mol. Sci. 2025, 26(14), 6588; https://doi.org/10.3390/ijms26146588 - 9 Jul 2025
Viewed by 578
Abstract
Ferroptosis is a type of cell death executed by phospholipid peroxidation in an iron-dependent manner. Ferroptosis plays a central role in inhibiting tumor growth, enhancing the immune response, and is now considered a strategy to combat resistance to anticancer therapies. The oncosuppressor p53 [...] Read more.
Ferroptosis is a type of cell death executed by phospholipid peroxidation in an iron-dependent manner. Ferroptosis plays a central role in inhibiting tumor growth, enhancing the immune response, and is now considered a strategy to combat resistance to anticancer therapies. The oncosuppressor p53 is one of the major regulators of ferroptosis and can either promote or inhibit ferroptosis, depending on the context and/or extent of the damage. p53 governs the transcription of many genes that modulate cell susceptibility to ferroptosis, using this manner of death to fulfill its role as tumor suppressor. The diverse functions of p53 are related to non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), since they can either regulate p53 or be regulated by p53. Therefore, an intricate metabolic network between ncRNAs and p53 ensures the correct response. In this review, we will discuss recent studies on the molecular interplay between p53-mediated ferroptosis and ncRNAs and how this contributes directly or indirectly to the outcome of ferroptosis. Full article
(This article belongs to the Section Molecular Oncology)
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30 pages, 8781 KiB  
Article
RNA-Seq Analysis of Mouse Hepatocytes AML12 Exposed to Neodymium Nitrate
by Ning Wang, Jing Leng, Yaxin Han, Gonghua Tao, Jingqiu Sun, Cheng Dong, Kelei Qian, Xiuli Chang, Ping Xiao and Xinyu Hong
Toxics 2025, 13(7), 573; https://doi.org/10.3390/toxics13070573 - 7 Jul 2025
Viewed by 484
Abstract
Objective: Neodymium nitrate (Nd(NO3)3) is widely used globally, raising concerns about its occupational and environmental safety. It enters the human body via the digestive system, accumulates in organs, and causes toxicity, including potential hepatotoxicity. However, the role of non-coding [...] Read more.
Objective: Neodymium nitrate (Nd(NO3)3) is widely used globally, raising concerns about its occupational and environmental safety. It enters the human body via the digestive system, accumulates in organs, and causes toxicity, including potential hepatotoxicity. However, the role of non-coding RNAs (ncRNAs) in Nd(NO3)3-induced liver injury remains unclear. This study aimed to identify key genes and regulatory pathways involved in Nd(NO3)3-induced hepatic injury using RNA sequencing (RNA-seq) and differential gene expression analysis. Methods: Mouse hepatocytes (AML12 cells) were exposed to Nd(NO3)3, and RNA-seq was performed to analyze the expression profiles of miRNA, lncRNA, circRNA, and mRNA. qPCR was used to validate the RNA-seq results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the functions and pathways associated with differentially expressed genes (DEGs). Results: Nd(NO3)3 exposure altered the expression of ferroptosis-related genes and induced significant changes in mRNA, miRNA, circRNA, and lncRNA expression levels. GO and KEGG analyses revealed that DEGs were closely related to cellular ferroptosis pathways. Specific miRNAs, lncRNAs, and circRNAs were significantly upregulated, suggesting their potential as biomarkers for Nd(NO3)3-induced ferroptosis and liver injury. Conclusion: This study provides the first comprehensive transcriptome database for Nd(NO3)3-induced liver injury, highlighting the involvement of ncRNAs in hepatotoxicity. These findings offer valuable insights for developing biomarkers and understanding the mechanisms underlying Nd(NO3)3-induced hepatic injury. Full article
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22 pages, 4262 KiB  
Article
Transcriptomic Changes of Telencephalon and Hypothalamus in Largemouth Bass (Micropterus salmoides) Under Crowding Stress
by Meijia Li, Leshan Yang and Ying Liu
Biology 2025, 14(7), 809; https://doi.org/10.3390/biology14070809 - 3 Jul 2025
Viewed by 400
Abstract
Crowding stress is an inevitable stressor in intensive farming, yet its underlying mechanisms are still obscure, severely hindering the aquaculture industry’s healthy development. As the primary sensory and regulatory organ for stressors, the brain plays a crucial role in stress responses. In this [...] Read more.
Crowding stress is an inevitable stressor in intensive farming, yet its underlying mechanisms are still obscure, severely hindering the aquaculture industry’s healthy development. As the primary sensory and regulatory organ for stressors, the brain plays a crucial role in stress responses. In this study, the effect of crowding stress on the telencephalon (Tel) and hypothalamus (Hy) has been explored using RNA sequencing. After four weeks of crowding stress, neuroinflammation-related genes were significantly induced in both the Tel and Hy. Additionally, cell fate-related processes were markedly altered. Neurogenesis-related pathways, including the Wnt and Hedgehog signaling pathways, were significantly enriched in both regions. The apoptosis-related genes (caspase3, p53) were predominantly downregulated in the Tel (log2Fold Change: −1.27 and −0.71, respectively), while ferroptosis-related genes (ho1, ncoa4) were specifically activated in the Hy (log2Fold Change: 1.15 and 0.73, respectively). The synaptic plasticity-related genes (prkcg, cacna1d) were significantly downregulated in both the Tel (log2Fold Change: −1.78 and −0.88) and Hy (log2Fold Change: −1.99 and −1.52). Furthermore, neurotransmitter synthesis (γ-aminobutyric acid (GABA) and serotonin (5-HT)) was disrupted in the Tel, whereas growth-related hormone gene expression was markedly altered in the Hy. These findings provide novel insights into the neurobiological mechanisms of chronic crowding stress in fish, laying a foundation for developing brain-targeted strategies to enhance welfare and mitigate stress in intensive largemouth bass farming. Full article
(This article belongs to the Special Issue Metabolic and Stress Responses in Aquatic Animals)
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21 pages, 6501 KiB  
Article
Bioinformatics-Driven Identification of Ferroptosis-Related Gene Signatures Distinguishing Active and Latent Tuberculosis
by Rakesh Arya, Hemlata Shakya, Viplov Kumar Biswas, Gyanendra Kumar, Sumendra Yogarayan, Harish Kumar Shakya and Jong-Joo Kim
Genes 2025, 16(6), 716; https://doi.org/10.3390/genes16060716 - 18 Jun 2025
Viewed by 686
Abstract
Background: Tuberculosis (TB) remains a major global public health challenge, and diagnosing it can be difficult due to issues such as distinguishing active TB from latent TB infection (LTBI), as well as the sample collection process, which is often time-consuming and lacks sensitivity [...] Read more.
Background: Tuberculosis (TB) remains a major global public health challenge, and diagnosing it can be difficult due to issues such as distinguishing active TB from latent TB infection (LTBI), as well as the sample collection process, which is often time-consuming and lacks sensitivity and specificity. Ferroptosis is emerging as an important factor in TB pathogenesis; however, its underlying molecular mechanisms are not fully understood. Thus, there is a critical need to establish ferroptosis-related diagnostic biomarkers for tuberculosis (TB). Methods: This study aimed to identify and validate potential ferroptosis-related genes in TB infection while enhancing clinical diagnostic accuracy through bioinformatics-driven gene identification. The microarray expression profile dataset GSE28623 from the Gene Expression Omnibus (GEO) database was used to identify ferroptosis-related differentially expressed genes (FR-DEGs) associated with TB. Subsequently, these genes were used for immune cell infiltration, Gene Set Enrichment Analysis (GSEA), functional enrichment and correlation analyses. Hub genes were identified using Weighted Gene Co-expression Network Analysis (WGCNA) and validated in independent datasets GSE37250, GSE39940, GSE19437, and GSE31348. Results: A total of 21 FR-DEGs were identified. Among them, four hub genes (ACSL1, PARP9, TLR4, and ATG3) were identified as diagnostic biomarkers. These biomarkers were enriched in immune-response related pathways and were validated. Immune cell infiltration, GSEA, functional enrichment and correlation analyses revealed that multiple immune cell types could be activated by FR-DEGs. Throughout anti-TB therapy, the expression of the four hub gene signatures significantly decreased in patients cured of TB. Conclusions: In conclusion, ferroptosis plays a key role in TB pathogenesis. These four hub gene signatures are linked with TB treatment effectiveness and show promise as biomarkers for differentiating TB from LTBI. Full article
(This article belongs to the Special Issue Advances in Bioinformatics of Human Diseases)
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18 pages, 5301 KiB  
Article
The Profile of Retinal Ganglion Cell Death and Cellular Senescence in Mice with Aging
by Wen-Ying Wang, Xin Bin, Yanxuan Xu, Si Chen, Shuyi Zhou, Shaowan Chen, Yingjie Cao, Kunliang Qiu and Tsz Kin Ng
Int. J. Mol. Sci. 2025, 26(12), 5436; https://doi.org/10.3390/ijms26125436 - 6 Jun 2025
Viewed by 2854
Abstract
Older age is a risk factor for glaucoma, in which progressive retinal ganglion cell (RGC) loss leads to visual field defects and irreversible visual impairment and even blindness. We recently identified the involvement of cellular senescence in RGC cell death post-optic nerve injury. [...] Read more.
Older age is a risk factor for glaucoma, in which progressive retinal ganglion cell (RGC) loss leads to visual field defects and irreversible visual impairment and even blindness. We recently identified the involvement of cellular senescence in RGC cell death post-optic nerve injury. Here we further aimed to delineate the profile of RGC survival in mice with aging, a physiological process with increasing cellular senescence. The numbers of senescent cells in the ganglion cell layer (GCL) significantly and progressively increased starting at 8 months of age. Yet, significant reduction of ganglion cell complex layer thickness began in the 10-month-old mice, and significant reduction in the number of RGCs began in the 12-month-old mice as compared to the 2-month-old mice. Meanwhile, pyroptosis and ferroptosis markers as well as cellular senescence-related cell cycle arrest proteins p15Ink4b, p16Ink4a, p21Cip1, and p53 were significantly and progressively increased in GCL. In contrast, there were no significant changes in dendritic field, complexity, and branches with increasing ages. Comparing between the 2- and 16-month-old mouse retinas, the differentially expressed genes were involved in the pathways of neurodegeneration, innate immunity, and mitochondrial ATP synthesis. In summary, this study revealed the gradual increase in senescent cells as well as pyroptosis and ferroptosis with progressive RGC reduction in mice with aging. Cellular senescence and the related cell death pathways are potential targets for age-related RGC reduction. Full article
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14 pages, 3817 KiB  
Article
Mechanism of Circadian Regulation in Ferroptosis of the BMAL1/NRF2 Pathway in Renal Ischemia–Reperfusion
by Shang Xu, Qiao Tang, Haiyang Du, Jiatao Xie, Ruoxin He, Ruiyan Wang and Qian Sun
Biomedicines 2025, 13(6), 1375; https://doi.org/10.3390/biomedicines13061375 - 4 Jun 2025
Viewed by 672
Abstract
Background: Renal ischemia–reperfusion injury (IRI) is a frequent cause of kidney transplant failure. Recent studies have shown that the extent of injury is closely linked to ferroptosis, and the process of cellular ferroptosis is diurnal and regulated by circadian genes. NRF2, [...] Read more.
Background: Renal ischemia–reperfusion injury (IRI) is a frequent cause of kidney transplant failure. Recent studies have shown that the extent of injury is closely linked to ferroptosis, and the process of cellular ferroptosis is diurnal and regulated by circadian genes. NRF2, involved in iron–heme metabolism, may be related to ferroptosis. We hypothesize that the pathway plays a role in circadian regulation in ferroptosis in renal IRI. Methods: Using hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK8), flow cytometry, real-time quantitative reverse transcription PCR (qRT-PCR), and Western blotting, we analyzed renal tubular tissues in vivo and in vitro and compared the groups with IR injury treatment, inhibition of ferroptosis, and inhibition of BMAL1 gene expression at the ZT0 (zeitgeber time 0) and ZT12 (zeitgeber time 12) time points. Results: IR injury treatments caused exacerbation of injury, both in vivo and in vitro, and were more pronounced at the ZT12 time point, which correlates with circadian rhythms. The use of the ferroptosis inhibitor (Fer-I) attenuated IR injury, suggesting that IRI is associated with ferroptosis. In contrast, reduced BMAL1-gene expression exacerbated injury, and NRF2, which is elevated in IR injury, was suppressed. Conclusions: The circadian gene BMAL1 affects the circadian rhythm of ferroptosis in renal IRI through the regulation of NRF2 and its downstream pathway. In this study, renal injury is well ameliorated by the ferroptosis inhibitor, exhibiting potential as a therapeutic agent for use in renal transplantation. Full article
(This article belongs to the Special Issue The Role of Iron in Human Diseases)
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24 pages, 5751 KiB  
Article
Identification of HMOX-1-Targeting Natural Compounds in Camellia nitidissima Chi for NSCLC Therapy: Integrating Bioassay and In Silico Screening Approaches
by Lingqiu Zhang, Fan Zhang, Haimei Liang, Xiangling Qin, Chunmei Liang, Manlu Zhong, Yuemi Mo, Jinling Xie, Xiaotao Hou, Jiagang Deng, Erwei Hao and Zhengcai Du
Pharmaceuticals 2025, 18(6), 824; https://doi.org/10.3390/ph18060824 - 30 May 2025
Viewed by 652
Abstract
Background/Objectives: Camellia nitidissima Chi (C. nitidissima), a traditional Chinese “food and medicine homology” plant, has demonstrated potential anti-tumor properties. However, its mechanisms of anti-lung cancer activity via ferroptosis remain unclear. This study aimed to construct an integrated research system of [...] Read more.
Background/Objectives: Camellia nitidissima Chi (C. nitidissima), a traditional Chinese “food and medicine homology” plant, has demonstrated potential anti-tumor properties. However, its mechanisms of anti-lung cancer activity via ferroptosis remain unclear. This study aimed to construct an integrated research system of “natural product extraction-purification, bioactivity evaluation, and computational drug screening” to explore the bioactive compounds in C. nitidissima leaves targeting HMOX-1-mediated ferroptosis and their anti-lung cancer mechanisms. Methods: Active fractions were prepared using ethanol extraction combined with polyamide column chromatography. The anti-lung cancer activity was evaluated using the NCI-H1975 cell model. Ferroptosis was verified via transmission electron microscopy (TEM), biochemical indicators, a PCR Array, and immunofluorescence. The bioactive compounds were identified using UPLC-Q Exactive MS, and their binding affinity to HMOX-1 was evaluated via molecular docking and dynamics simulations, followed by cellular validation. Results: The 95% F1 fraction from the extracts of C. nitidissima leaves exhibited the strongest anti-lung cancer activity, which could be significantly reversed by Ferrostatin-1. Furthermore, it induced typical ferroptosis-related structural damage in mitochondria, including shrinkage and a reduction in size, increased membrane density, and a reduction or even the disappearance of cristae structures. At the molecular level, this fraction significantly increased the levels of oxidative stress markers (ROS↑, MDA↑, Fe2+↑, and GSH↓) and upregulated the expression of key ferroptosis-related genes, including HMOX-1, CHAC1, and NOX1. Using UPLC-Q Exactive MS combined with computational simulation methods, four bioactive compounds with high affinity for HMOX1 were successfully identified, including isochlorogenic acid A (−8.4 kcal/mol), isochlorogenic acid C (−8.4 kcal/mol), apigenin (−7.8 kcal/mol), and chrysin (−7.3 kcal/mol). Cellular experiments validated that these compounds exhibited dose-dependent anti-proliferative effects. Conclusions: The leaves of C. nitidissima induce anti-lung cancer effects via HMOX-1-mediated ferroptosis. Isochlorogenic acid A/C, apigenin, and chrysin were identified as key bioactive components. These findings lay the foundation for the development of natural ferroptosis-targeted drugs. Full article
(This article belongs to the Section Natural Products)
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24 pages, 21945 KiB  
Article
Drug Pair of Astragali Radix–Ligustri Lucidi Fructus Alleviates Acute Kidney Injury in Mice Induced by Ischemia–Reperfusion Through Inhibiting Ferroptosis
by Xuanhe Liu, Dan Zhang, Yuting Xie, Mengdan Wang, Xiaochun Chen, Weijie Yu, Yuming Ma, Jia Zeng, Qixuan Long, Guangrui Huang, Jie Geng and Anlong Xu
Pharmaceuticals 2025, 18(6), 789; https://doi.org/10.3390/ph18060789 - 25 May 2025
Viewed by 767
Abstract
Background: Acute kidney injury (AKI), characterized by high morbidity and mortality, is primarily caused by renal ischemia–reperfusion injury (RIRI). Ferroptosis plays a key role in RIRI, yet its underlying mechanisms remain unclear. The drug pair of Astragali Radix–Ligustri Lucidi Fructus (DAL) shows promise [...] Read more.
Background: Acute kidney injury (AKI), characterized by high morbidity and mortality, is primarily caused by renal ischemia–reperfusion injury (RIRI). Ferroptosis plays a key role in RIRI, yet its underlying mechanisms remain unclear. The drug pair of Astragali Radix–Ligustri Lucidi Fructus (DAL) shows promise in renal diseases, but its protective effects against RIRI and associated molecular pathways via ferroptosis inhibition are unknown. This study aimed to investigate DAL’s therapeutic effects on RIRI and its mechanisms. Methods: A mouse model of bilateral renal ischemia–reperfusion was established. Renal function (serum creatinine, Scr; blood urea nitrogen, BUN), inflammatory cytokines (TNF-α, IFN-γ, IL-6), ferroptosis markers (GPX4, MDA, GSH, tissue iron), and pathological damage were evaluated. Transcriptomic sequencing and electron microscopy analyzed gene pathways and mitochondrial structure. In HK-2 cells, oxygen–glucose deprivation/reoxygenation (OGD/R) and RSL3-induced ferroptosis models were used to assess DAL-containing serum effects via cell viability, GPX4 expression, and mitochondrial morphology. LC-MS analyzed DAL’s chemical components, and network pharmacology predicted ferroptosis-related targets. Results: DAL significantly reduced Scr/BUN levels, alleviated tubular injury, fibrosis, and apoptosis, and downregulated inflammatory cytokines and damage markers. It inhibited ferroptosis by upregulating GPX4, decreasing MDA/tissue iron, and increasing GSH. Transcriptomics revealed enrichment in lipid metabolism pathways. DAL restored the mitochondrial cristae structure; DAL-containing serum improved cell viability, blocked RSL3-induced GPX4 downregulation, and mitigated mitochondrial dysfunction. Network pharmacology identified DAL’s potential active components and targets. Molecular docking validated binding affinity and interaction patterns of active components with targets. Conclusions: DAL protects against RIRI by upregulating GPX4, preserving the mitochondrial structure, and inhibiting ferroptosis, highlighting its therapeutic potential for AKI prevention and treatment. Full article
(This article belongs to the Special Issue New Development in Pharmacotherapy of Kidney Diseases)
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18 pages, 3224 KiB  
Article
Astilbin Alleviates IL-17-Induced Hyperproliferation and Inflammation in HaCaT Cells via Inhibiting Ferroptosis Through the cGAS-STING Pathway
by Xiaohan Xu, Huizhong Zhang, Aqian Chang, Hulinyue Peng, Shiman Li, Ke Zhang, Wenqi Wang, Xingbin Yin, Changhai Qu, Xiaoxv Dong and Jian Ni
Int. J. Mol. Sci. 2025, 26(11), 5075; https://doi.org/10.3390/ijms26115075 - 24 May 2025
Viewed by 915
Abstract
Psoriasis, a chronic inflammatory skin disorder, is driven by dysregulated immune responses and keratinocyte dysfunction. Here, we explore the therapeutic potential of Astilbin (AST), a flavonoid with potent anti-inflammatory properties, in modulating ferroptosis and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) [...] Read more.
Psoriasis, a chronic inflammatory skin disorder, is driven by dysregulated immune responses and keratinocyte dysfunction. Here, we explore the therapeutic potential of Astilbin (AST), a flavonoid with potent anti-inflammatory properties, in modulating ferroptosis and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in IL-17-stimulated HaCaT keratinocytes. Our psoriatic cell model recapitulated key pathological features, including hyperproliferation, membrane integrity loss, mitochondrial dysfunction, and heightened oxidative stress, alongside elevated proinflammatory cytokine levels. Ferroptosis-related biomarkers were significantly altered, with increased malondialdehyde (MDA) accumulation, reduced glutathione (GSH) levels, iron overload (Fe2+), and enhanced lipid peroxidation (detected via C11-BODIPY). Mechanistically, mitochondrial damage triggered cytoplasmic leakage of mitochondrial DNA (mtDNA), activating the cGAS-STING pathway, as evidenced by upregulated pathway-associated protein expression. AST intervention effectively mitigated these pathological changes by suppressing ferroptosis and modulating cGAS-STING signaling. These findings reveal a dual-pathway regulatory mechanism, positioning AST as a promising therapeutic candidate for psoriasis. By elucidating the interplay between ferroptosis and the cGAS-STING pathway, this study provides new insights into psoriatic inflammation and offers a rationale for targeting these pathways in therapeutic strategies. Full article
(This article belongs to the Section Molecular Pharmacology)
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17 pages, 712 KiB  
Article
Association of Functional Gene Variants in DYSF–ZNF638, MTSS1 and Ferroptosis-Related Genes with Multiple Sclerosis Severity and Target Gene Expression
by Tamara Djuric, Ana Djordjevic, Jovana Kuveljic, Milan Stefanovic, Evica Dincic, Ana Kolakovic and Maja Zivkovic
Int. J. Mol. Sci. 2025, 26(11), 4986; https://doi.org/10.3390/ijms26114986 - 22 May 2025
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Abstract
Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq on ferroptosis-related genes in distinctive MS phenotypes, we selected putative regulatory variants in the top three DEGs (CDKN1A, MAP1B and EGLN2) and investigated their association with gene expression, plasma/serum parameters and disease severity (EDSS, MSSS, gARMSS). The study included 604 patients with relapsing–remitting (RR) and 241 with progressive (P) MS. The variants CDKN1A rs3176326 and rs3176336, EGLN2 rs111833532, MAP1B rs62363242 and rs1217817 with the previously reported DYSF-ZNF638 locus rs10191329, and MTSS1 rs9643199 were genotyped using TaqMan®, and the HLA-DRB1*15:01 status was also determined. Significant association of the rare MAP1B rs62363242 allele with PMS in females, independent of HLA-DRB1*1501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. CDKN1A haplotypes were significantly associated with CDKN1A mRNA levels in RRMS and SPMS patients. RAB4B-EGLN2 locus rs111833532 and DYSF-ZNF638 locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of CDKN1A, a part of the p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor and critical regulator of the response to hypoxia, variant rs111833532, along with DYSF-ZNF638 locus rs10191329, was associated with clinical severity. The indicated, novel, sex-specific association of MAP1B rs62363242 with the course of MS remains to be validated in larger studies. Full article
(This article belongs to the Special Issue Molecular Research and Treatment in Multiple Sclerosis)
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