Antioxidants & redox signaling最新文献

{"title":"miR-208a-3p Targets PPP6C to Regulate the Progression of Radiation-Induced Pneumonia.","authors":"Lixin Gong, Yi Liu, Jinyu Wang, Zhe Zhao, Wenfang Duan, Yu Xiao, Haibo Peng, Long Zhao, Mouna Khouchani, Takoui Abdelmajid, Nadia Aittahssaint, Tao He, Zhiqiang Jiang, Jingyi Li","doi":"10.1089/ars.2023.0459","DOIUrl":"10.1089/ars.2023.0459","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Radiation-induced pneumonia (RP) is a common complication after radiotherapy for clinical thoracic tumors, and increasing evidence suggests that miRNAs have potential value in regulating radiation-induced lung injury. However, the potential mechanism is still obscure. Here, we evaluated the miRNAs-dependent mechanism involved in the progression of RP. <b><i>Results:</i></b> Our data showed that mmu-miR-208a-3p was consistently highly expressed in the lung tissue of irradiated mice. <i>In vitro</i> studies demonstrated that the expression of miR-208a-3p in cells was significantly increased after X-ray irradiation. Further mechanism studies indicated that radiation-induced upregulation of miR-208a-3p promoted inflammatory responses by suppressing the expression of protein phosphatase 6C (PPP6C) and activating the cyclic GMP-AMP synthase/stimulator of interferon genes protein pathway. Overexpression of PPP6C can alleviate radiation-induced DNA damage and excessive accumulation of ROS. It was also observed that PPP6C inhibited ionizing RP <i>in vivo</i>. <b><i>Innovation and Conclusion:</i></b> miR-208a-3p/PPP6C represents a potential therapeutic target for RP which needs to be verified by future clinical studies. <i>Antioxid. Redox Signal.</i> 43, 239-253.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"239-253"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the HNRNPA2B1/HDGF/PTN Axis to Overcome Radioresistance in Non-Small Cell Lung Cancer.","authors":"Fushi Han, Shuzhen Chen, Kangwei Zhang, Kunming Zhang, Meng Wang, Peijun Wang","doi":"10.1089/ars.2024.0808","DOIUrl":"10.1089/ars.2024.0808","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Radioresistance in non-small cell lung cancer (NSCLC) presents a major barrier to effective treatment. This study explores the molecular mechanisms underlying this resistance, focusing on the heterogeneous nuclear ribonucleoprotein A2B1/hepatoma-derived growth factor/pleiotrophin (HNRNPA2B1/HDGF/PTN) signaling pathway and its role in autophagy-dependent ferroptosis regulation. Our aim is to uncover how this pathway contributes to tumor cell survival under radiotherapy stress, thereby identifying potential therapeutic targets to overcome radioresistance. <b><i>Results:</i></b> We developed radiotherapy-resistant lung cancer cell lines and assessed their proliferation and migration capabilities through Cell Counting Kit-8 and Transwell assays, respectively. Single-cell RNA sequencing revealed significant differences in gene expression profiles between radioresistance and radiation-sensitive cells. Functional studies, including immunofluorescence, flow cytometry, and biochemical staining, confirmed that radioresistance was associated with enhanced autophagy and altered ferroptosis. Furthermore, HNRNPA2B1 knockdown reduced the expression of Ki67 and proliferating cell nuclear antigen, markers of proliferation, in a mouse tumor model. In addition, modulation of HNRNPA2B1 affected protein interactions and N6-methyladenosine RNA modifications, as demonstrated by reverse transcription-quantitative polymerase chain reaction, Western blot, and methylation RNA immunoprecipitation-quantitative PCR. <b><i>Innovation:</i></b> This study provides new insights into how the HNRNPA2B1/HDGF/PTN pathway promotes radioresistance by influencing autophagy-dependent ferroptosis. This mechanism represents a potential vulnerability that could be therapeutically targeted to improve radiotherapy efficacy in lung cancer. <b><i>Conclusion:</i></b> Our findings demonstrate that the HNRNPA2B1/HDGF/PTN signaling pathway plays a crucial role in sustaining radioresistant phenotypes by modulating autophagy and ferroptosis. Targeting this pathway may enhance the therapeutic response in NSCLC, offering a novel strategy to combat treatment resistance. <i>Antioxid. Redox Signal.</i> 43, 189-214.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"189-214"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons.","authors":"Wenyao Yang, Bruce Thompson, Sara Miellet, Marnie Maddock, Marek Napierala, Mirella Dottori, Faith Kwa","doi":"10.1089/ars.2024.0756","DOIUrl":"10.1089/ars.2024.0756","url":null,"abstract":"<p><p><b><i>Aims:</i></b> In Friedreich ataxia (FRDA), early motor discoordination stems from dysfunctional sensory neurons in the spinal cord driven by epigenetic dysregulation, frataxin (FXN) deficiency, oxidative stress, and inflammation. Omaveloxolone, a nuclear factor erythroid 2-related factor-2 (NRF2) inducer, is the only treatment available. In various chronic disease models, sulforaphane (SF) can target NRF2 and the above processes. This study compared the effects of SF with omaveloxolone and dimethyl fumarate (DMF) in sensory neurons generated from FRDA patient-induced pluripotent stem cells and their isogenic control. <b><i>Results:</i></b> The successful generation of the FRDA and isogenic control sensory neurons was confirmed by the positive expression of β-III TUBULIN, BRN3A, ISLET1, PERIPHERIN, and tropomyosin receptor kinase C. In comparison with the isogenic control, FRDA sensory neurons displayed an aberrant gene expression profile alike to that reported in patients. None of the drugs affected the viability of the isogenic control sensory neurons. SF treatment improved the viability of FRDA sensory neurons by up to 61% versus the untreated control. DMF treatment showed a modest 35% increase, while omaveloxolone lacked an effect. SF-treated FRDA sensory neurons demonstrated increased reduced glutathione/oxidized glutathione ratio and expression of FXN and redox markers, and a reduced expression of selected epigenetic enzymes and inflammatory cytokines, at the respective gene and protein levels. DMF and omaveloxolone treatments only modulated some of these biomarkers. <b><i>Innovation:</i></b> We revealed the therapeutic potential of SF and how it performs in comparison with omaveloxolone and DMF, in a physiologically and genetically relevant <i>in vitro</i> FRDA model. <b><i>Conclusion:</i></b> SF offers a multipronged approach to alleviating the different cellular events underlying FRDA. <i>Antioxid. Redox Signal.</i> 43, 308-327.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"308-327"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox Differences Between Neurons and Astrocytes <i>In Vivo</i> in Ischemic Brain Tissues of Rodents.","authors":"Daria A Kotova, Aleksandra D Ivanova, Ilya V Kelmanson, Kseniia I Morozova, Yulia V Khramova, Maxim A Solotenkov, Evgeny A Stepanov, Aleksandr A Moshchenko, Alisa B Tiaglik, Anna A Fedotova, Anton V Zalygin, Vladimir A Oleinikov, Alexey G Katrukha, Alexey Semyanov, Vsevolod V Belousov, Andrei B Fedotov, Ilya V Fedotov, Nadezda A Brazhe, Dmitry S Bilan","doi":"10.1089/ars.2024.0876","DOIUrl":"10.1089/ars.2024.0876","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Reactive oxygen species (ROS) are considered to play a key damaging role in brain during the development of ischemic stroke. To clarify how different ROS contribute to ischemic pathogenesis, innovative approaches for real-time <i>in vivo</i> detection of redox parameters are necessary. <b><i>Results:</i></b> Using highly sensitive genetically encoded biosensor HyPer7 and a fiber-optic neurointerface technology, we demonstrated that the level of hydrogen peroxide (H₂O₂) slowly increases in neurons and astrocytes of the ischemic area of the rat brain after middle cerebral artery occlusion during next 40 h; notably, in astrocytes the level is somewhat higher. Raman microspectroscopy in awake mice also revealed redox differences between mitochondria of neurons and astrocytes during acute ischemia caused by photothrombosis. Astrocytes demonstrated the overloading of the electron transport chain (ETC) with electrons after 1 h of ischemia, whereas neurons do not demonstrate changes in the amount of reduced electron carries. <b><i>Innovation and Conclusion:</i></b> The combination of novel <i>in vivo</i> approaches allows to detail redox events with spatiotemporal resolution. We demonstrated redox difference between neurons and astrocytes in damaged brain areas <i>in vivo</i>. An elevated loading of astrocytic ETC with electrons during the acute ischemia phase provides basis for the increased generation of superoxide anion radical (O₂^•-) with its following conversion to other reactive species. However, we observed increased H₂O₂ concentrations in astrocytes and neurons at later pathogenesis stages. During this period, ETC did not demonstrate an elevated loading with electrons, and therefore, increased H₂O₂ generation may be a phenomenon of secondary redox events. <i>Antioxid. Redox Signal.</i> 43, 272-287.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"272-287"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small Molecules Targeting Non-Coding RNAs Regulating Ferroptosis: New Opportunities in Precision Cancer Therapy.","authors":"Junjing Zhang, Yan Wang, Joshua S Fleishman, Weihua Zheng, Hongquan Wang, Fanyu Meng, Yumin Wang","doi":"10.1089/ars.2024.0807","DOIUrl":"10.1089/ars.2024.0807","url":null,"abstract":"<p><p>Ferroptosis, a distinct form of regulated cell death (RCD), has emerged as a promising approach for cancer treatment owing to its potential to inhibit tumor malignancy. Research indicates that non-coding RNAs (ncRNAs) regulate ferroptosis susceptibility in cancer cells through epigenetic modifications. ncRNAs play essential roles in cancer initiation, metastasis, and drug resistance. Findings indicate that small-molecule compounds (SMCs) target ncRNAs to regulate ferroptosis, providing new opportunities for precision cancer therapy. Therefore, this review aims to elucidate current molecular mechanisms underlying ncRNA-mediated ferroptosis regulation in cancer and investigate the potential of SMCs as therapeutic agents to modulate this process, offering a new strategy for precision in cancer treatment. This review also summarizes the innovative strategy of targeting ncRNAs with SMCs, a therapeutic approach for regulating ferroptosis and transforming the landscape of cancer treatment. Overall, it highlights a novel strategy for cancer therapy by pharmacologically targeting the ncRNA-ferroptosis axis with SMCs. <i>Antioxid. Redox Signal.</i> 43, 345-362.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"345-362"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NADPH Oxidase with APX-115: Suppression of Platelet Activation and Thrombotic Response.","authors":"Joara Jang, Hyunseong Yu, Eun Bee Oh, Ji Won Park, Solee Kim, Taeryeong Kim, Jisue Sohn, Bo-Ram Jin, Tong-Shin Chang","doi":"10.1089/ars.2024.0695","DOIUrl":"10.1089/ars.2024.0695","url":null,"abstract":"<p><p><b><i>Aims:</i></b> NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are critical for platelet activation and thrombus formation. We hypothesized that inhibiting NOX-mediated ROS production with a pan-NOX inhibitor, APX-115, could effectively suppress platelet activation and thrombus formation, potentially serving as a novel antiplatelet therapeutic. This study aimed to explore the effects of APX-115 on human platelet functional responses and ROS-mediated signaling pathways. <b><i>Results:</i></b> APX-115 inhibited intracellular and extracellular ROS production in collagen-stimulated platelets, suppressing aggregation, P-selectin exposure, and ATP release. By preserving protein tyrosine phosphatase activity, APX-115 reduced tyrosine phosphorylation-dependent pathways inhibition, including spleen tyrosine kinase, LAT, Vav1, Bruton's tyrosine kinase, and phospholipase Cγ2, leading to decreased PKC activation and calcium mobilization. APX-115 also suppressed collagen-induced integrin αIIbβ3 activation, accompanied by elevated cGMP and vasodilator-stimulated phosphoprotein phosphorylation levels. In addition, APX-115 reduced p38 MAPK and ERK5 activation, leading to diminished phospholipase A2 phosphorylation, thromboxane production, and the exposure of procoagulant phosphatidylserine. These inhibitory effects extended to thrombus development caused by platelet adherence under shear and arterial thrombosis without prolonging bleeding time in murine models. <b><i>Innovation:</i></b> This study is the first to demonstrate that APX-115 inhibits NOX-mediated ROS production, platelet activation, and thrombus formation. By uncovering its effects on collagen receptor glycoprotein VI-mediated pathways, the work highlights the promise of APX-115 as an antiplatelet and antithrombotic agent. <b><i>Conclusion:</i></b> Our findings highlight the therapeutic potential of APX-115 in treating thrombotic and cardiovascular disorders by targeting NOX-mediated ROS production to mitigate platelet hyperreactivity and thrombus formation. <i>Antioxid. Redox Signal.</i> 43, 288-307.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"288-307"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Tocopherol Ameliorates Liver Fibrosis by Inhibiting Hepatic Stellate Cell Activation by Promoting Nrf2 Nuclear Translocation.","authors":"Rui Fang, Xue Wang, Han Zhang, Xiaolin Xie, Huan Chen, Wenting Lu, Si Zhao, Tianming Zhao, Zihao Cai, Ming Zhang, Bing Xu, Yuzheng Zhuge, Feng Zhang","doi":"10.1177/15230864251364900","DOIUrl":"https://doi.org/10.1177/15230864251364900","url":null,"abstract":"<p><p><b><i>Aims:</i></b> α-Tocopherol is a potent natural antioxidant with a variety of biological functions and is widely used in clinical practice. However, the effect and mechanism of α-tocopherol on liver fibrosis remain unknown. The core of liver fibrosis is the activation of hepatic stellate cell (HSC). Inhibiting HSC activation may be the underlying mechanism by which α-tocopherol alleviates liver fibrosis. <b><i>Results:</i></b> Our study revealed that α-tocopherol improved liver injury and fibrosis in both CCl₄ and bile duct ligation induced liver fibrosis model mice. α-Tocopherol inhibited HSC activation by promoting nuclear erythroid 2-related factor 2 (Nrf2) translocation into the nucleus. α-Tocopherol directly promoted Nrf2 nuclear translocation by reducing its degradation, additionally, α-tocopherol suppressed autophagy by inhibiting endoplasmic reticulum stress, resulting in increased SQSTM1 competition to bind KEAP1 and indirectly promoting Nrf2 translocation into the nucleus. The increased Nrf2 nuclear translocation upregulated the expression of antioxidant genes, thereby reducing ROS and subsequently inhibiting HSC activation. Moreover, the antifibrotic and hepatoprotective effects of α-tocopherol were verified by the addition of the Nrf2 activator-curcumin, the autophagy inhibitor-3-methyladenine and the endoplasmic reticulum stress inhibitor-sodium 4-phenylbutyrate. <b><i>Innovation and Conclusion:</i></b> Our study is the first to identify the mechanism by which α-tocopherol alleviates liver fibrosis. Broadly speaking, this study demonstrated that α-tocopherol promotes Nrf2 nuclear translocation by reducing Nrf2 degradation and inhibiting endoplasmic reticulum stress, which then inhibits HSC activation and ultimately ameliorates liver injury and fibrosis. Therefore, α-tocopherol may become a novel therapeutic strategy for liver fibrosis. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Ammonia-Induced Brain Endothelial Senescence: Role of miRNA-183-5p.","authors":"Karolina Orzeł-Gajowik, Krzysztof Milewski, Marta Obara-Michlewska, Aleksandra Ellert-Miklaszewska, Aneta Magiera, Karina Kwapiszewska, Magdalena Zielińska","doi":"10.1089/ars.2024.0784","DOIUrl":"10.1089/ars.2024.0784","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Hyperammonemia, defined by elevated ammonia levels, may co-occur in various neurological disorders, but its effects on cerebrovascularity are not fully understood. This study aimed to investigate how hyperammonemia affects brain endothelial cells senescence and selected within <i>in silico</i> analysis micro RNA-183-5p in this process. <b><i>Results:</i></b> Reduction in cerebrovascular density in hyperammonemia-induced rats, similar to that seen in 12-month-old rats, using von Willebrand factor staining, was observed. MicroRNA (miRNA) profile analysis of the brain cortex and plasma identified miRNA-183-5p contributing to endothelial senescence. <i>In vitro</i> studies of ammonia-treated rat brain endothelial cell line 4 showed senescent features, including increased β-galactosidase activity, higher mRNA levels and fluorescence intensity of p16 and p21, and altered senescence-associated secretory phenotype. Additionally, the transfection of miRNA-183-5p mimic induced similar senescent characteristics in endothelial cells, whereas miRNA-183-5p mimic inhibition reversed some effects. <b><i>Innovation:</i></b> This study is the first to link hyperammonemia-induced cerebrovascular dysfunction with miRNA-183-5p, highlighting its role in promoting endothelial senescence. The findings suggest that miRNA-183-5p could be a target for therapeutic interventions, preventing ammonia-induced brain endothelial dysfunction. <b><i>Conclusion:</i></b> Hyperammonemia promotes brain endothelial cells senescence through miRNA-183-5p, reducing cerebrovascular density. This may contribute to cerebral dysfunction seen in hyperammonemia-associated neurological disorders. Targeting miRNA-183-5p could offer a novel therapeutic strategy to mitigate endothelial dysfunction and preserve brain health in hyperammonemia. <i>Antioxid. Redox Signal.</i> 43, 254-271.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"254-271"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of the Zinc Transporter ZIP13 (Slc39a13) Leads to Ferroptosis by Inhibiting Mitochondrial Iron-Sulfur Cluster Biosynthesis and Induces Ischemia/Reperfusion Injury in Mouse Hearts.","authors":"Rui Zhang, Jiannan Wang, Qing Yang, Yonghao Yu, Xinxin Cheng, Zhelong Xu","doi":"10.1089/ars.2024.0815","DOIUrl":"10.1089/ars.2024.0815","url":null,"abstract":"<p><p><b><i>Aims:</i></b> While ferroptosis is involved in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury, the exact mechanism underlying the induction of ferroptosis by I/R remains elusive. Since downregulation of Zrt, Irt-like protein 13 (ZIP13) plays a role in I/R injury by targeting mitochondria, we hypothesized that ZIP13 downregulation during I/R leads to ferroptosis through a mitochondria-dependent mechanism. <b><i>Results:</i></b> ZIP13 cKO (cardiac-specific conditional knockout) induced ferroptosis and suppressed mitochondrial iron-sulfur cluster (ISC) biosynthesis. ZIP13 cKO also reduced glutathione levels as well as solute carrier family 7 member 11 (SLC7A11) expression. Moreover, cKO increased mitochondrial Fe²⁺ levels. Similar to the action of cKO, I/R led to ZIP13 downregulation, ferroptosis, mitochondrial Fe²⁺ accumulation, and suppression of ISC biosynthesis. In support, cKO of ZIP13 aggravated I/R-induced ferroptosis and mitochondrial Fe²⁺ accumulation. In contrast, ZIP13 overexpression prevented I/R-induced ferroptosis, mitochondrial Fe²⁺ accumulation, and suppression of ISC biosynthesis. Finally, ferrostatin-1, a ferroptosis inhibitor, alleviated I/R-induced ferroptosis as well as cardiac injury in cKO mice. <b><i>Innovation:</i></b> This study proposes a previously unknown mechanism by which ZIP13 downregulation contributes to ferroptosis in the setting of myocardial I/R. <b><i>Conclusions:</i></b> These findings highlight that ZIP13 downregulation at reperfusion triggers ferroptosis by suppressing the mitochondrial ISC biosynthesis followed by mitochondrial Fe²⁺ accumulation. Downregulation of SLC7A11 may also contribute to the action of ZIP13 downregulation. <i>Antioxid. Redox Signal.</i> 43, 328-344.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"328-344"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remifentanil Mitigates Hepatic Ischemia/Reperfusion-Induced D1-Medium Spiny Neurons Damage via Fibroblast Growth Factor 18 Upregulation.","authors":"Yujuan You, Xianliang Xing, Binquan Tang, Huanling Deng, Enjun Lei, Yiguo Wu","doi":"10.1089/ars.2024.0892","DOIUrl":"https://doi.org/10.1089/ars.2024.0892","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Hepatic ischemia/reperfusion (I/R) injury induces liver damage and secondary neuronal injury, particularly in D1-medium spiny neurons (D1-MSNs). This study investigates whether remifentanil exerts neuroprotective effect by regulating oxidative stress and inflammation <i>via</i> fibroblast growth factor 18 (FGF18) upregulation. <b><i>Results:</i></b> Remifentanil markedly attenuated liver and striatal injury in a murine I/R model, as indicated by decreased serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, along with reduced inflammatory cytokines interleukin 1 beta and interleukin 18. Oxidative stress was mitigated through enhanced activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and reduced reactive oxygen species levels, confirmed by lower dihydroethidium and mitochondrial superoxide indicator red fluorescence. Neuronal injury was alleviated, demonstrated by improved D1-MSN morphology, reduced apoptosis, increased expression of D1-dopamine receptor and Substance P, and fewer c-Fos-positive cells. Transcriptomic and machine learning analyses identified FGF18 as a key mediator of remifentanil's neuroprotective effects. Functional studies further confirmed that FGF18 overexpression reduced neuronal damage, whereas its knockdown abolished the protective effects of remifentanil, highlighting its pivotal role. <b><i>Innovation:</i></b> This study is the first to demonstrate that remifentanil exerts neuroprotective effects in hepatic I/R injury by upregulating FGF18, providing new insights into its combined hepatoprotective and neuroprotective mechanisms. <b><i>Conclusion:</i></b> Remifentanil mitigates hepatic I/R-induced injury to D1-MSNs by upregulating FGF18, thereby reducing oxidative stress and inflammation while preserving neuronal structure and function. These findings identify FGF18 as a potential therapeutic target for liver I/R-related neurological damage. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}