Pub Date : 2026-02-01Epub Date: 2025-12-03DOI: 10.1016/j.redox.2025.103961
Ding Liu , Yuanzhi Ye , Zirong Lan , An Chen , Xingchen Zhou , Zhenhao Li , Xin Wen , Jisheng Xiao , Fan Ouyang , Jianyun Yan
Vascular calcification, prevalent in patients with chronic kidney disease, atherosclerosis, and diabetes, is strongly associated with elevated cardiovascular morbidity and mortality, highlighting the urgent need for effective treatments. Oxidative stress is a key contributor to the progression of vascular calcification. Nanozymes, nanomaterials with enzyme-like catalytic properties, exhibit strong reactive oxygen species (ROS) scavenging abilities and good biocompatibility, making them promising therapeutic candidates. This study aims to investigate whether polyvinylpyrrolidone (PVP)-functionalized ultrasmall Cu2-xSe nanoparticles (CSP NPs) act as nanozymes for treating vascular calcification. In vitro, CSP NPs significantly inhibit calcification of rat and human vascular smooth muscle cells (VSMCs) and reduce the expression of osteogenic markers Runx2 and BMP2. Moreover, CSP NPs alleviate calcification of rat and human arterial rings. In a mouse model, CSP NPs localize to certain areas, such as the aortic arch and abdominal aortas, and are safely metabolized by the liver and kidneys without organ toxicity. Further analyses confirm that CSP NPs inhibit mouse and chronic kidney disease (CKD) rat aortic calcification. Mechanistically, CSP NPs inhibit oxidative stress and mitochondrial dysfunction. Additionally, CSP NPs decrease the expression of NF-κB and NLRP3, thus reducing the levels of inflammatory cytokines IL-1β and IL-6. CSP NPs suppress NLRP3 activator-induced calcification in VSMCs and arterial rings. This study provides the first evidence that CSP NPs alleviate vascular calcification by inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation, suggesting a promising therapeutic approach.
{"title":"Ultrasmall Cu2−xSe nanoparticles alleviate vascular calcification through inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation","authors":"Ding Liu , Yuanzhi Ye , Zirong Lan , An Chen , Xingchen Zhou , Zhenhao Li , Xin Wen , Jisheng Xiao , Fan Ouyang , Jianyun Yan","doi":"10.1016/j.redox.2025.103961","DOIUrl":"10.1016/j.redox.2025.103961","url":null,"abstract":"<div><div>Vascular calcification, prevalent in patients with chronic kidney disease, atherosclerosis, and diabetes, is strongly associated with elevated cardiovascular morbidity and mortality, highlighting the urgent need for effective treatments. Oxidative stress is a key contributor to the progression of vascular calcification. Nanozymes, nanomaterials with enzyme-like catalytic properties, exhibit strong reactive oxygen species (ROS) scavenging abilities and good biocompatibility, making them promising therapeutic candidates. This study aims to investigate whether polyvinylpyrrolidone (PVP)-functionalized ultrasmall Cu<sub>2-x</sub>Se nanoparticles (CSP NPs) act as nanozymes for treating vascular calcification. <em>In vitro</em>, CSP NPs significantly inhibit calcification of rat and human vascular smooth muscle cells (VSMCs) and reduce the expression of osteogenic markers Runx2 and BMP2. Moreover, CSP NPs alleviate calcification of rat and human arterial rings. In a mouse model, CSP NPs localize to certain areas, such as the aortic arch and abdominal aortas, and are safely metabolized by the liver and kidneys without organ toxicity. Further analyses confirm that CSP NPs inhibit mouse and chronic kidney disease (CKD) rat aortic calcification. Mechanistically, CSP NPs inhibit oxidative stress and mitochondrial dysfunction. Additionally, CSP NPs decrease the expression of NF-κB and NLRP3, thus reducing the levels of inflammatory cytokines IL-1β and IL-6. CSP NPs suppress NLRP3 activator-induced calcification in VSMCs and arterial rings. This study provides the first evidence that CSP NPs alleviate vascular calcification by inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation, suggesting a promising therapeutic approach.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103961"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-28DOI: 10.1016/j.redox.2025.103950
Ling Zhu , Qimei Tan , Yuxia Wang , Lihong Hong , Chen Chen , Lingyi Kong , Jianguang Luo
Colorectal cancer (CRC), propelled by extreme molecular heterogeneity and intractable drug resistance, is rapidly becoming a global health challenge. Ferroptosis offers a promising therapeutic strategy by exploiting the iron addiction and oxidative vulnerability of CRC cells. However, available methods to trigger ferroptosis are still limited, mostly focusing on antioxidant systems or iron metabolism. Here, we found that artemisitene (ATT), a bioactive natural sesquiterpene isolated from Artemisia annua, acted as a CRC therapeutic agent by promoting calcium-dependent ferroptosis. Integrative transcriptomics revealed that ATT repressed cytochrome P450 family 24 subfamily A member 1 (CYP24A1) expression, the pivotal mediator of this response. The ensuing calcium overload downregulated stearoyl-CoA desaturase (SCD) by CAMKK2/AMPK/SREBF1 axis, enriching oxidizable fatty acids and sensitizing CRC cells to lethal lipid peroxidation. Mechanistically, ATT was found to directly target lymphoid-specific helicase (LSH), covalently binding to the Cys205 residue of LSH and thereby disrupting its interaction with EWS RNA binding protein 1 (EWSR1). This disruption ultimately suppressed CYP24A1 transcription. Our findings revealed that pharmacological blockade of the LSH/CYP24A1/SCD axis triggers calcium-driven ferroptosis, positioning ATT as a potent, mechanism-based therapeutic for CRC.
{"title":"Artemisitene triggers calcium-dependent ferroptosis by disrupting the LSH-EWSR1 interaction in colorectal cancer","authors":"Ling Zhu , Qimei Tan , Yuxia Wang , Lihong Hong , Chen Chen , Lingyi Kong , Jianguang Luo","doi":"10.1016/j.redox.2025.103950","DOIUrl":"10.1016/j.redox.2025.103950","url":null,"abstract":"<div><div>Colorectal cancer (CRC), propelled by extreme molecular heterogeneity and intractable drug resistance, is rapidly becoming a global health challenge. Ferroptosis offers a promising therapeutic strategy by exploiting the iron addiction and oxidative vulnerability of CRC cells. However, available methods to trigger ferroptosis are still limited, mostly focusing on antioxidant systems or iron metabolism. Here, we found that artemisitene (ATT), a bioactive natural sesquiterpene isolated from <em>Artemisia annua</em>, acted as a CRC therapeutic agent by promoting calcium-dependent ferroptosis. Integrative transcriptomics revealed that ATT repressed cytochrome P450 family 24 subfamily A member 1 (CYP24A1) expression, the pivotal mediator of this response. The ensuing calcium overload downregulated stearoyl-CoA desaturase (SCD) by CAMKK2/AMPK/SREBF1 axis, enriching oxidizable fatty acids and sensitizing CRC cells to lethal lipid peroxidation. Mechanistically, ATT was found to directly target lymphoid-specific helicase (LSH), covalently binding to the Cys205 residue of LSH and thereby disrupting its interaction with EWS RNA binding protein 1 (EWSR1). This disruption ultimately suppressed CYP24A1 transcription. Our findings revealed that pharmacological blockade of the LSH/CYP24A1/SCD axis triggers calcium-driven ferroptosis, positioning ATT as a potent, mechanism-based therapeutic for CRC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103950"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-11DOI: 10.1016/j.redox.2025.103975
Kerri L.M. Smith , Philippe Pasdois , Mafalda Pires , Mitchell C. Lock , Gina L.J. Galli
A lack of oxygen during fetal development (fetal hypoxia) permanently alters the structure and function of the heart, leading to increased susceptibility to ischemia reperfusion (IR) injury in adulthood. However, the underlying cellular mechanisms are incompletely understood. In this study, we used a rat model to understand the role of calcium, reactive oxygen species and the mitochondrial permeability transition pore (MPTP) in programming IR sensitivity in offspring from hypoxic pregnancies. Pregnant Wistar rats were subjected to either ambient oxygen (∼21 %) throughout gestation, 13 % oxygen from gestational day 6–20, or 10.5 % oxygen from gestational day 15–20 (rat term ∼ 22 days). Offspring were raised to adulthood and hearts were subjected to ex vivo IR injury during Langendorff perfusion, whilst measuring ventricular pressure, intracellular calcium, oxidative stress and NAD(P)H autofluorescence. In addition, calcium retention capacity (CRC) and MPTP components were measured in isolated mitochondria, as well as basal H2O2 emission and electron transport system activity. Exposure to fetal hypoxia (10.5 % oxygen) increased IR sensitivity in adult offspring, demonstrated by increased diastolic pressure (p < 0.05), lipid peroxidation (p < 0.05), and an increased rate of NAD(P)H oxidation (p < 0.05) at reperfusion. This increased sensitivity to IR was associated with a decreased CRC (p < 0.01), increased basal H2O2 emission (p < 0.05) and decreased basal respiratory capacity linked to complex IV (p < 0.01). Additionally, both models of fetal hypoxia (13 % and 10.5 %) increased the abundance of the MPTP regulatory protein cyclophilin D in adult hearts (p < 0.01 and <0.001, respectively). Together, these data suggest that exposure to hypoxia during fetal development can programme MPTP calcium sensitivity by altering factors that modulate the pore (e.g. H2O2 emission, electron transport system activity, NAD(P)H oxidation and CypD content). These data could help to explain why individuals from hypoxic pregnancies are more susceptible to myocardial infarction, and other cardiovascular diseases.
{"title":"Fetal programming of the cardiac mitochondrial permeability transition pore in male offspring from hypoxic pregnancies","authors":"Kerri L.M. Smith , Philippe Pasdois , Mafalda Pires , Mitchell C. Lock , Gina L.J. Galli","doi":"10.1016/j.redox.2025.103975","DOIUrl":"10.1016/j.redox.2025.103975","url":null,"abstract":"<div><div>A lack of oxygen during fetal development (fetal hypoxia) permanently alters the structure and function of the heart, leading to increased susceptibility to ischemia reperfusion (IR) injury in adulthood. However, the underlying cellular mechanisms are incompletely understood. In this study, we used a rat model to understand the role of calcium, reactive oxygen species and the mitochondrial permeability transition pore (MPTP) in programming IR sensitivity in offspring from hypoxic pregnancies. Pregnant Wistar rats were subjected to either ambient oxygen (∼21 %) throughout gestation, 13 % oxygen from gestational day 6–20, or 10.5 % oxygen from gestational day 15–20 (rat term ∼ 22 days). Offspring were raised to adulthood and hearts were subjected to <em>ex vivo</em> IR injury during Langendorff perfusion, whilst measuring ventricular pressure, intracellular calcium, oxidative stress and NAD(P)H autofluorescence. In addition, calcium retention capacity (CRC) and MPTP components were measured in isolated mitochondria, as well as basal H<sub>2</sub>O<sub>2</sub> emission and electron transport system activity. Exposure to fetal hypoxia (10.5 % oxygen) increased IR sensitivity in adult offspring, demonstrated by increased diastolic pressure (<em>p</em> < 0.05), lipid peroxidation (<em>p</em> < 0.05), and an increased rate of NAD(P)H oxidation (<em>p</em> < 0.05) at reperfusion. This increased sensitivity to IR was associated with a decreased CRC (<em>p</em> < 0.01), increased basal H<sub>2</sub>O<sub>2</sub> emission (<em>p</em> < 0.05) and decreased basal respiratory capacity linked to complex IV (<em>p</em> < 0.01). Additionally, both models of fetal hypoxia (13 % and 10.5 %) increased the abundance of the MPTP regulatory protein cyclophilin D in adult hearts (<em>p</em> < 0.01 and <0.001, respectively). Together, these data suggest that exposure to hypoxia during fetal development can programme MPTP calcium sensitivity by altering factors that modulate the pore (e.g. H<sub>2</sub>O<sub>2</sub> emission, electron transport system activity, NAD(P)H oxidation and CypD content). These data could help to explain why individuals from hypoxic pregnancies are more susceptible to myocardial infarction, and other cardiovascular diseases.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103975"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-22DOI: 10.1016/j.redox.2025.103991
Fan Yang , Pengcheng Pang , Kang Yang , Xinyu Niu , Fang Cheng , Wei Li
Blood-brain barrier impairment (BBB) is the pathological basis of diabetic cognitive dysfunction. Brain microvascular endothelial cells (BMECs) are one of the most mitochondria-rich cell types within the BBB. Mitochondrial dysfunction in BMECs is defined as a pivotal event in diabetic cognitive dysfunction; however, the underlying mechanisms remain poorly understood. Protein phosphatase targeting COQ7 (PPTC7) was screened from RNA-sequencing analysis and its role in regulating mitochondrial function was in both in vitro and in vivo models. PPTC7 expression was predominantly upregulated in BMECs of type 2 diabetes mellitus mice. Genetic manipulations using short hairpin RNA and endothelial-specific adeno-associated virus were applied to investigate the effects of PPTC7 in diabetic cognitive dysfunction. PPTC7 deficiency upregulated mitochondrial oxidative phosphorylation, mitochondrial membrane potential, and mitophagy, but downregulated mitochondrial reactive oxygen species levels in BMECs. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays demonstrated the interaction of PPTC7 with prohibitin 2 (PHB2). PPTC7 disrupts mitochondrial function in BMECs via PHB2 by promoting its ubiquitin-proteasome degradation, which in turn aggravates BBB damage and contributes to diabetic cognitive dysfunction.
{"title":"Upregulation of PPTC7 in brain microvascular endothelial cell aggravates diabetic cognitive dysfunction by impairing PHB2 mediated mitochondrial function","authors":"Fan Yang , Pengcheng Pang , Kang Yang , Xinyu Niu , Fang Cheng , Wei Li","doi":"10.1016/j.redox.2025.103991","DOIUrl":"10.1016/j.redox.2025.103991","url":null,"abstract":"<div><div>Blood-brain barrier impairment (BBB) is the pathological basis of diabetic cognitive dysfunction. Brain microvascular endothelial cells (BMECs) are one of the most mitochondria-rich cell types within the BBB. Mitochondrial dysfunction in BMECs is defined as a pivotal event in diabetic cognitive dysfunction; however, the underlying mechanisms remain poorly understood. Protein phosphatase targeting COQ7 (PPTC7) was screened from RNA-sequencing analysis and its role in regulating mitochondrial function was in both in vitro and in vivo models. PPTC7 expression was predominantly upregulated in BMECs of type 2 diabetes mellitus mice. Genetic manipulations using short hairpin RNA and endothelial-specific adeno-associated virus were applied to investigate the effects of PPTC7 in diabetic cognitive dysfunction. PPTC7 deficiency upregulated mitochondrial oxidative phosphorylation, mitochondrial membrane potential, and mitophagy, but downregulated mitochondrial reactive oxygen species levels in BMECs. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays demonstrated the interaction of PPTC7 with prohibitin 2 (PHB2). PPTC7 disrupts mitochondrial function in BMECs via PHB2 by promoting its ubiquitin-proteasome degradation, which in turn aggravates BBB damage and contributes to diabetic cognitive dysfunction.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103991"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-30DOI: 10.1016/j.redox.2025.103956
Chang Yeop Han , Alexander E. St John , Jung Heon Kim , Xu Wang , Kristyn M. Ringgold , Lauren E. Neidig , Ronald Berenson , Susan A. Stern , Nathan J. White
Trauma-induced coagulopathy (TIC) induces anticoagulation and increases bleeding mortality. Inflammation and oxidative stress play an unknown role in TIC. We examined plasma from injured human trauma patients presenting to the Emergency Department compared to healthy controls to elucidate the contribution of inflammation and oxidative stress to anticoagulation during TIC. Trauma patients demonstrated coagulopathy by prolongation of clotting time assays and decreased thrombin generation in addition to increased pro-inflammatory cytokines and increased markers of oxidative stress. Clotting factors seven (FVII), ten (FX), and twelve (FXII) were oxidatively modified without quantitative changes, displaying decreased activity after trauma. Factor five (FV) was decreased in concentration and retained normal activity. Factor eight (FVIII) concentration and activity were increased after trauma. Clotting factor oxidation after exposure to activated human leukocytes in vitro also impaired thrombin generation and reproduced the oxidative and functional changes seen in trauma patients. Both antioxidant and anti-inflammatory treatments prevented clotting factor oxidation and TIC after trauma in vivo using a rodent TIC model. These results suggest that inflammation and oxidative stress contribute directly to anticoagulation during TIC by direct and selective oxidation of clotting factors. FXII may make a novel contribution to the pathophysiology of TIC by its oxidation.
{"title":"Inflammation contributes to trauma-induced coagulopathy by oxidation of multiple clotting factors","authors":"Chang Yeop Han , Alexander E. St John , Jung Heon Kim , Xu Wang , Kristyn M. Ringgold , Lauren E. Neidig , Ronald Berenson , Susan A. Stern , Nathan J. White","doi":"10.1016/j.redox.2025.103956","DOIUrl":"10.1016/j.redox.2025.103956","url":null,"abstract":"<div><div>Trauma-induced coagulopathy (TIC) induces anticoagulation and increases bleeding mortality. Inflammation and oxidative stress play an unknown role in TIC. We examined plasma from injured human trauma patients presenting to the Emergency Department compared to healthy controls to elucidate the contribution of inflammation and oxidative stress to anticoagulation during TIC. Trauma patients demonstrated coagulopathy by prolongation of clotting time assays and decreased thrombin generation in addition to increased pro-inflammatory cytokines and increased markers of oxidative stress. Clotting factors seven (FVII), ten (FX), and twelve (FXII) were oxidatively modified without quantitative changes, displaying decreased activity after trauma. Factor five (FV) was decreased in concentration and retained normal activity. Factor eight (FVIII) concentration and activity were increased after trauma. Clotting factor oxidation after exposure to activated human leukocytes <em>in vitro</em> also impaired thrombin generation and reproduced the oxidative and functional changes seen in trauma patients. Both antioxidant and anti-inflammatory treatments prevented clotting factor oxidation and TIC after trauma <em>in vivo</em> using a rodent TIC model. These results suggest that inflammation and oxidative stress contribute directly to anticoagulation during TIC by direct and selective oxidation of clotting factors. FXII may make a novel contribution to the pathophysiology of TIC by its oxidation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103956"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-15DOI: 10.1016/j.redox.2025.103977
Wa Li , Zihui Tang , Jiyang Xue
In head and neck squamous cell carcinoma, a “cold” (immune-desert) tumor microenvironment promotes immunosuppression, which is a critical driver of disease recurrence and therapeutic resistance. To address this challenge, we develop an innovative strategy to remodel the tumor immune microenvironment by disrupting intracellular redox balance to induce ferroptosis and immunogenic cell death, synergistically activating STING pathway to facilitating the transition of tumors from a “cold” to a “hot” immunophenotype. In this study, hyaluronic acid-functionalized hollow manganese dioxide nanoparticles loading β-lapachone (hMnL), engineered for targeted chemo-immunotherapy is constructed. In vitro investigations reveal that hMnL induces robust reactive oxygen species (ROS) generation, triggering ferroptosis and immunogenic cell death. Concurrently, Mn2+ ions released from hMnL in response to the acidic tumor microenvironment activate the STING pathway, fostering dendritic cell (DC) maturation and M1 macrophage polarization. Activation of the ferroptosis and immune-related pathways was indicated by transcriptome sequencing, which identified significantly differentially expressed genes (e.g., Fth1, Hmox1, Calr). In vivo, hMnL exhibits superior tumor-targeting efficacy and sustained intratumoral retention, culminating in potent tumor growth suppression. Furthermore, hMnL activates STING pathway in tumor, leading to enhanced CD8+ T cell infiltration, and a marked reduction in regulatory T cell (Treg) populations. Additionally, hMnL also shows good immunoprotective effects and long-term biosafety. These findings establish hMnL as a promising therapeutic platform that integrates targeted chemotherapy with immune modulation, offering a potent strategy to overcome immunosuppression and improve clinical outcomes in cancer.
{"title":"Synergistic STING activation and oxidative cascades-induced ferroptosis drive tumor microenvironment remodeling by engineered manganese nanoreactors","authors":"Wa Li , Zihui Tang , Jiyang Xue","doi":"10.1016/j.redox.2025.103977","DOIUrl":"10.1016/j.redox.2025.103977","url":null,"abstract":"<div><div>In head and neck squamous cell carcinoma, a “cold” (immune-desert) tumor microenvironment promotes immunosuppression, which is a critical driver of disease recurrence and therapeutic resistance. To address this challenge, we develop an innovative strategy to remodel the tumor immune microenvironment by disrupting intracellular redox balance to induce ferroptosis and immunogenic cell death, synergistically activating STING pathway to facilitating the transition of tumors from a “cold” to a “hot” immunophenotype. In this study, hyaluronic acid-functionalized hollow manganese dioxide nanoparticles loading β-lapachone (hMnL), engineered for targeted chemo-immunotherapy is constructed. <em>In vitro</em> investigations reveal that hMnL induces robust reactive oxygen species (ROS) generation, triggering ferroptosis and immunogenic cell death. Concurrently, Mn<sup>2+</sup> ions released from hMnL in response to the acidic tumor microenvironment activate the STING pathway, fostering dendritic cell (DC) maturation and M1 macrophage polarization. Activation of the ferroptosis and immune-related pathways was indicated by transcriptome sequencing, which identified significantly differentially expressed genes (e.g., <em>Fth1</em>, <em>Hmox1</em>, <em>Calr</em>). <em>In vivo</em>, hMnL exhibits superior tumor-targeting efficacy and sustained intratumoral retention, culminating in potent tumor growth suppression. Furthermore, hMnL activates STING pathway in tumor, leading to enhanced CD8<sup>+</sup> T cell infiltration, and a marked reduction in regulatory T cell (Treg) populations. Additionally, hMnL also shows good immunoprotective effects and long-term biosafety. These findings establish hMnL as a promising therapeutic platform that integrates targeted chemotherapy with immune modulation, offering a potent strategy to overcome immunosuppression and improve clinical outcomes in cancer.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103977"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-12DOI: 10.1016/j.redox.2025.103971
Raviranjan Pandey , Arpan Narayan Roy , Sandip Sarkar , Rakiba Rohman , Kaustav Chakraborty , Rupa Bargakshatriya , Sanjana Pandey , Pruthwiraj , Debosmita Bhattacharya , Saurav Kumar , Saptarshi Maji , Aidan T. Pezacki , Sumit K. Pramanik , Christopher J. Chang , Ashima Bhattacharjee , Neelanjana Sengupta , Amitava Das , Arnab Gupta
Loss-of-function mutations in copper-ATPase ATP7B underlie Wilson disease (WD), a disorder characterized by hepatic copper accumulation and severe hepato-neuropathology. Existing chelation therapeutics remove excess copper but lack intrinsic antioxidant capacity and frequently cause systemic toxicity. Here we evaluate melatonin, an FDA-approved indoleamine with antioxidant and putative metal-chelating activity, as a candidate therapeutic for WD. In ATP7B−/- hepatocytes, melatonin restored copper-induced reactive oxygen species (ROS) to basal levels, reduced apoptosis twofold, and attenuated Nrf2 nuclear translocation leading to reduction of Hemoxygenase-1 abundance. Live-cell ratiometric analysis of GSSG/GSH using GRX1-roGFP2 expressed in melatonin-treated ATP7B−/- hepatocytes revealed a significant reduction in intensity-ratio, indicating an effective mitigation of copper-induced glutathione oxidation. Isothermal calorimetric titration revealed a moderate Cu2+ affinity (KaITC = 4.54 × 103 M−1), yet melatonin produced a stronger reduction in cellular oxidative stress than either d-penicillamine or N-acetylcysteine, underscoring its cooperative antioxidant–chelation advantage. Melatonin (MLT) copper chelation was also rationalized by MD-simulations and DFT framework showing thermodynamically favourable interaction via amide–Cu2+ coordination. In-cellulo studies also revealed that copper-induced vesicularized ATP7B reinstates to Golgi in melatonin-treated hepatocytes. In vivo, melatonin treatment reduced copper-induced oxidative stress in zebrafish embryos and lowered copper burden in Caenorhabditis elegans WD model. Our studies revealed that encapsulation of melatonin within an engineered polymeric nanocapsules having dithiol linkers, susceptible to cleavage by GSH, extended melatonin's circulatory half-life ten-fold and enhanced its ROS-scavenging efficacy three-fold relative to free melatonin. This work introduces a unique dual-function therapeutic strategy that integrates antioxidant activity with copper chelation, simultaneously addressing copper overload and redox imbalance. Repurposing melatonin, with its established clinical safety, offers rapid and cost-effective translational pathway toward WD-therapy while providing a generalizable platform for redox- and metal-associated disorders.
{"title":"Repurposing melatonin's therapeutic potential in Wilson disease: Addressing copper overload and redox imbalance","authors":"Raviranjan Pandey , Arpan Narayan Roy , Sandip Sarkar , Rakiba Rohman , Kaustav Chakraborty , Rupa Bargakshatriya , Sanjana Pandey , Pruthwiraj , Debosmita Bhattacharya , Saurav Kumar , Saptarshi Maji , Aidan T. Pezacki , Sumit K. Pramanik , Christopher J. Chang , Ashima Bhattacharjee , Neelanjana Sengupta , Amitava Das , Arnab Gupta","doi":"10.1016/j.redox.2025.103971","DOIUrl":"10.1016/j.redox.2025.103971","url":null,"abstract":"<div><div>Loss-of-function mutations in copper-ATPase ATP7B underlie Wilson disease (WD), a disorder characterized by hepatic copper accumulation and severe hepato-neuropathology. Existing chelation therapeutics remove excess copper but lack intrinsic antioxidant capacity and frequently cause systemic toxicity. Here we evaluate melatonin, an FDA-approved indoleamine with antioxidant and putative metal-chelating activity, as a candidate therapeutic for WD. In ATP7B<sup>−/-</sup> hepatocytes, melatonin restored copper-induced reactive oxygen species (ROS) to basal levels, reduced apoptosis twofold, and attenuated Nrf2 nuclear translocation leading to reduction of Hemoxygenase-1 abundance. Live-cell ratiometric analysis of GSSG/GSH using GRX1-roGFP2 expressed in melatonin-treated ATP7B<sup>−/-</sup> hepatocytes revealed a significant reduction in intensity-ratio, indicating an effective mitigation of copper-induced glutathione oxidation. Isothermal calorimetric titration revealed a moderate Cu<sup>2+</sup> affinity (K<sub>a</sub><sup>ITC</sup> = 4.54 × 10<sup>3</sup> M<sup>−1</sup>), yet melatonin produced a stronger reduction in cellular oxidative stress than either <span>d</span>-penicillamine or N-acetylcysteine, underscoring its cooperative antioxidant–chelation advantage. Melatonin (MLT) copper chelation was also rationalized by MD-simulations and DFT framework showing thermodynamically favourable interaction via amide–Cu<sup>2+</sup> coordination. <em>In-cellulo</em> studies also revealed that copper-induced vesicularized ATP7B reinstates to Golgi in melatonin-treated hepatocytes. <em>In vivo</em>, melatonin treatment reduced copper-induced oxidative stress in zebrafish embryos and lowered copper burden in <em>Caenorhabditis elegans</em> WD model. Our studies revealed that encapsulation of melatonin within an engineered polymeric nanocapsules having dithiol linkers, susceptible to cleavage by GSH, extended melatonin's circulatory half-life ten-fold and enhanced its ROS-scavenging efficacy three-fold relative to free melatonin. This work introduces a unique dual-function therapeutic strategy that integrates antioxidant activity with copper chelation, simultaneously addressing copper overload and redox imbalance. Repurposing melatonin, with its established clinical safety, offers rapid and cost-effective translational pathway toward WD-therapy while providing a generalizable platform for redox- and metal-associated disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103971"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-15DOI: 10.1016/j.redox.2025.103978
Fengchen Zhang , Tao Lv , Tianqi Xu , Jie Li , Jie Lian , Siyu Lin , Qin Hu , Yichao Jin , Feng Jia , Xiaohua Zhang
Lipid droplet accumulation in microglia has been implicated in inflammatory functions associated with aging and demyelinating diseases. However, the molecular mechanisms driving lipid droplet formation under pathological conditions remain unrevealed. It is demonstrated herein that the acetylation of fatty acid synthase (FASN) plays a key regulatory role in the accumulation of lipid droplets in microglia following traumatic brain injury (TBI). Through mass spectrometry analysis, we identified hyperacetylation at lysine K673 of FASN as a critical driver of lipid droplet formation in microglia. Notably, this acetylation event not only promotes lipid droplet accumulation but also enhances pro-inflammatory cytokine production and phagocytic activity in microglia. Additionally, we found that HDAC3 may be the enzyme responsible for deacetylation of FASN K673. Importantly, observation of a mouse model carrying the FASN K673R mutation revealed a reduction in microglial lipid droplet accumulation and neuroinflammatory responses following TBI relative to wild-type mice. Thus, FASN acetylation is a pivotal regulator of post-TBI microglial lipid droplet formation and neuroinflammation. This positions the targeting of deacetylation pathways as a novel therapeutic strategy for TBI.
{"title":"Acetylation of fatty acid synthase regulates microglial lipid droplets accumulation and pro-inflammatory activity following traumatic brain injury","authors":"Fengchen Zhang , Tao Lv , Tianqi Xu , Jie Li , Jie Lian , Siyu Lin , Qin Hu , Yichao Jin , Feng Jia , Xiaohua Zhang","doi":"10.1016/j.redox.2025.103978","DOIUrl":"10.1016/j.redox.2025.103978","url":null,"abstract":"<div><div>Lipid droplet accumulation in microglia has been implicated in inflammatory functions associated with aging and demyelinating diseases. However, the molecular mechanisms driving lipid droplet formation under pathological conditions remain unrevealed. It is demonstrated herein that the acetylation of fatty acid synthase (FASN) plays a key regulatory role in the accumulation of lipid droplets in microglia following traumatic brain injury (TBI). Through mass spectrometry analysis, we identified hyperacetylation at lysine K673 of FASN as a critical driver of lipid droplet formation in microglia. Notably, this acetylation event not only promotes lipid droplet accumulation but also enhances pro-inflammatory cytokine production and phagocytic activity in microglia. Additionally, we found that HDAC3 may be the enzyme responsible for deacetylation of FASN K673. Importantly, observation of a mouse model carrying the FASN K673R mutation revealed a reduction in microglial lipid droplet accumulation and neuroinflammatory responses following TBI relative to wild-type mice. Thus, FASN acetylation is a pivotal regulator of post-TBI microglial lipid droplet formation and neuroinflammation. This positions the targeting of deacetylation pathways as a novel therapeutic strategy for TBI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103978"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-18DOI: 10.1016/j.redox.2025.103986
Xuan Liu , Yue Hao , Shanlong Tang , Xiusong Li , Liang Chen , Hongfu Zhang
High concentrations of particulate matter (PM) in poultry housing act as carriers for microbial aerosols, with Gram-negative bacteria and their outer membrane components—outer membrane proteins (OMPs) and lipopolysaccharide (LPS)—playing pivotal roles in disrupting redox homeostasis. This review systematically examines how OMPs and LPS drive mitochondrial dysfunction and oxidative damage, proposing the “mitochondrial-ROS axis” as an integrative framework to explain their convergent mechanisms. We evaluate evidence that OMPs promote iron dysregulation, target mitochondria, and initiate apoptotic signaling, whereas LPS triggers robust mitochondrial ROS bursts via TLR4/MyD88 and TRAF6-ECSIT pathways, leading to NLRP3 inflammasome activation and pyroptosis. And we further clarify the dynamic conflict between pathogen attack, mediated through the oxidative bursts of OMPs and LPS, and host reductive defenses, including peroxisomal activity, thioredoxin and glutathione systems, and uncoupling proteins. While this axis provides a useful predictive model for anticipating oxidative stress intensity and inflammatory activation, its applicability has notable constraints—such as the context-dependence of ROS in cell-fate decisions and the need for further avian-specific validation of key pathways. This synthesis provides a balanced perspective. Future studies should prioritize avian-specific validation of key pathways and elucidate the temporal dynamics and tissue specificity of ROS responses to inform targeted interventions in poultry health.
{"title":"Gram-negative bacterial outer membrane proteins and lipopolysaccharides key factors linking chicken coop environment and oxidative stress","authors":"Xuan Liu , Yue Hao , Shanlong Tang , Xiusong Li , Liang Chen , Hongfu Zhang","doi":"10.1016/j.redox.2025.103986","DOIUrl":"10.1016/j.redox.2025.103986","url":null,"abstract":"<div><div>High concentrations of particulate matter (PM) in poultry housing act as carriers for microbial aerosols, with Gram-negative bacteria and their outer membrane components—outer membrane proteins (OMPs) and lipopolysaccharide (LPS)—playing pivotal roles in disrupting redox homeostasis. This review systematically examines how OMPs and LPS drive mitochondrial dysfunction and oxidative damage, proposing the “mitochondrial-ROS axis” as an integrative framework to explain their convergent mechanisms. We evaluate evidence that OMPs promote iron dysregulation, target mitochondria, and initiate apoptotic signaling, whereas LPS triggers robust mitochondrial ROS bursts via TLR4/MyD88 and TRAF6-ECSIT pathways, leading to NLRP3 inflammasome activation and pyroptosis. And we further clarify the dynamic conflict between pathogen attack, mediated through the oxidative bursts of OMPs and LPS, and host reductive defenses, including peroxisomal activity, thioredoxin and glutathione systems, and uncoupling proteins. While this axis provides a useful predictive model for anticipating oxidative stress intensity and inflammatory activation, its applicability has notable constraints—such as the context-dependence of ROS in cell-fate decisions and the need for further avian-specific validation of key pathways. This synthesis provides a balanced perspective. Future studies should prioritize avian-specific validation of key pathways and elucidate the temporal dynamics and tissue specificity of ROS responses to inform targeted interventions in poultry health.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103986"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-06DOI: 10.1016/j.redox.2025.103963
Kristina Lossow , Maria Maares , Tom Heinze , Denny Pellowski , Elisa Richter , Karolin Schröder , Lars Dahmen , Christoph Schüßler , Kostja Renko , Tanja Schwerdtle , Hajo Haase , Anna P. Kipp
Trace elements such as copper, zinc, and selenium are essential micronutrients that play crucial roles in various physiological processes, mainly through their involvement in enzymes and regulatory proteins. A deficiency of any of these elements can impair physiological functions and lead to a range of symptoms. While copper deficiency is rare, e.g., vegans are particularly susceptible to inadequate intake of zinc and selenium. To investigate the effects of multiple simultaneous deficiencies, a feeding study was conducted in adult male and female C57BL/6Jrj mice receiving diets low in copper, zinc, and selenium. This approach enabled us to explore potential interactions between trace elements and to identify organ-specific effects based on their distribution profiles. We observed a substantial depletion of copper and selenium concentrations in the circulation and in almost all organs although to a varying extent. In contrast, zinc levels were well maintained and only declined in serum and bone. In line with the well-known antagonistic relationship between copper and zinc, our findings revealed that zinc deficiency mitigated symptoms of copper deficiency, which was most pronounced in female mice. Moreover, copper deficiency led to increased selenium concentrations in various organs, which, however, was not accompanied by generally higher selenoprotein expression. Therefore, it is essential to consider potential effects of single trace element deficiencies on other trace elements taking also combined effects into account.
{"title":"Distribution interactions of the trace elements zinc, copper, and selenium under conditions of their parallel deficiency","authors":"Kristina Lossow , Maria Maares , Tom Heinze , Denny Pellowski , Elisa Richter , Karolin Schröder , Lars Dahmen , Christoph Schüßler , Kostja Renko , Tanja Schwerdtle , Hajo Haase , Anna P. Kipp","doi":"10.1016/j.redox.2025.103963","DOIUrl":"10.1016/j.redox.2025.103963","url":null,"abstract":"<div><div>Trace elements such as copper, zinc, and selenium are essential micronutrients that play crucial roles in various physiological processes, mainly through their involvement in enzymes and regulatory proteins. A deficiency of any of these elements can impair physiological functions and lead to a range of symptoms. While copper deficiency is rare, e.g., vegans are particularly susceptible to inadequate intake of zinc and selenium. To investigate the effects of multiple simultaneous deficiencies, a feeding study was conducted in adult male and female C57BL/6Jrj mice receiving diets low in copper, zinc, and selenium. This approach enabled us to explore potential interactions between trace elements and to identify organ-specific effects based on their distribution profiles. We observed a substantial depletion of copper and selenium concentrations in the circulation and in almost all organs although to a varying extent. In contrast, zinc levels were well maintained and only declined in serum and bone. In line with the well-known antagonistic relationship between copper and zinc, our findings revealed that zinc deficiency mitigated symptoms of copper deficiency, which was most pronounced in female mice. Moreover, copper deficiency led to increased selenium concentrations in various organs, which, however, was not accompanied by generally higher selenoprotein expression. Therefore, it is essential to consider potential effects of single trace element deficiencies on other trace elements taking also combined effects into account.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103963"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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