Chronic exposure to fine particulate matter (PM2.5) and insulin resistance (IR) are each linked to Alzheimer’s disease (AD), but IR has not been systematically positioned as a mechanistic conduit through which PM2.5 heightens AD vulnerability. Drawing on epidemiological, animal, and cellular studies, this review outlines converging pathways along a PM2.5-IR-AD axis: chronic neuroinflammation, oxidative stress and mitochondrial dysfunction, blood-brain barrier disruption, and impaired amyloid-β (Aβ) clearance. Across sections, study-specific limitations are comprehensively discussed. Positioning IR as a central node linking PM2.5 exposure to AD reframes air pollution as a modifiable metabolic-neurologic risk. Potential therapeutic and preventive avenues are also highlighted. Future work could prioritize longitudinal and interventional studies that directly interrogate the PM2.5-IR-AD triad and refine biomarkers to guide precision prevention.
慢性暴露于细颗粒物（PM2.5）和胰岛素抵抗（IR）都与阿尔茨海默病（AD）有关，但IR尚未被系统地定位为PM2.5增加AD易感性的机制管道。根据流行病学、动物和细胞研究，本综述概述了沿PM2.5-IR-AD轴的趋同途径：慢性神经炎症、氧化应激和线粒体功能障碍、血脑屏障破坏和淀粉样蛋白-β (a β)清除受损。在各个章节中，全面讨论了特定研究的局限性。将IR定位为PM2.5暴露与AD之间的中心节点，将空气污染重新定义为可改变的代谢神经风险。还强调了潜在的治疗和预防途径。未来的工作可以优先考虑直接询问PM2.5-IR-AD三元组的纵向和介入性研究，并完善生物标志物以指导精确预防。
{"title":"Smog, sugar, and synapses: Unraveling the PM2.5-insulin resistance-Alzheimer’s disease axis","authors":"Hsuan-Yu Huang , Yu-Yin Huang , Chia-Lin Wu , Wei-Chien Huang , Chih-Ho Lai","doi":"10.1016/j.redox.2026.104031","DOIUrl":"10.1016/j.redox.2026.104031","url":null,"abstract":"<div><div>Chronic exposure to fine particulate matter (PM2.5) and insulin resistance (IR) are each linked to Alzheimer’s disease (AD), but IR has not been systematically positioned as a mechanistic conduit through which PM2.5 heightens AD vulnerability. Drawing on epidemiological, animal, and cellular studies, this review outlines converging pathways along a PM2.5-IR-AD axis: chronic neuroinflammation, oxidative stress and mitochondrial dysfunction, blood-brain barrier disruption, and impaired amyloid-β (Aβ) clearance. Across sections, study-specific limitations are comprehensively discussed. Positioning IR as a central node linking PM2.5 exposure to AD reframes air pollution as a modifiable metabolic-neurologic risk. Potential therapeutic and preventive avenues are also highlighted. Future work could prioritize longitudinal and interventional studies that directly interrogate the PM2.5-IR-AD triad and refine biomarkers to guide precision prevention.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104031"},"PeriodicalIF":11.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962518","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 : 2026-01-14DOI: 10.1016/j.redox.2026.104032
B. Chen , J.U. Mayer
Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis.
While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation.
Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.
{"title":"Emerging frontiers in the mitochondrial regulation of dendritic cell biology","authors":"B. Chen , J.U. Mayer","doi":"10.1016/j.redox.2026.104032","DOIUrl":"10.1016/j.redox.2026.104032","url":null,"abstract":"<div><div>Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis.</div><div>While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation.</div><div>Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104032"},"PeriodicalIF":11.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995158","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 : 2026-01-13DOI: 10.1016/j.redox.2026.104027
Ernesto Muñoz-Palma , Natali Acosta-Tapia , Cristopher Villablanca , Carlos Wilson , Cecilia Hidalgo , Christian González-Billault
NMDA Receptors (NMDARs) have essential functions in the nervous system, including neuronal maturation, neurotransmission, synaptic plasticity, learning, and memory. However, reports regarding the roles of glutamate and NMDARs during early neuronal development are not available. Here, we present results showing that glutamate release and NMDARs regulate neuronal polarity acquisition. NMDARs loss- and gain-of-function antagonistically modulated neuronal polarization and axonal elongation. An intracellular mechanism involving Ca2+ release from the endoplasmic reticulum, activation of the Rho GTPase Rac1, actin cytoskeleton rearrangements at the axonal growth cone, and H2O2 production coupled these morphological changes. Optogenetic Rac1 activation simultaneously promoted lamellipodia formation and H2O2 production suggesting functional coupling between these seemingly unconnected events. The mechanism presented here involves a dual function for the Rac1 protein that depends on glutamate and NMDAR activity. We propose that glutamate and NMDARs, via a complex set of signaling pathways, promote early neuronal development and axonal growth.
{"title":"NMDAR and glutamate control axon growth by regulating Rac1-dependent actin dynamics and H2O2 production","authors":"Ernesto Muñoz-Palma , Natali Acosta-Tapia , Cristopher Villablanca , Carlos Wilson , Cecilia Hidalgo , Christian González-Billault","doi":"10.1016/j.redox.2026.104027","DOIUrl":"10.1016/j.redox.2026.104027","url":null,"abstract":"<div><div>NMDA Receptors (NMDARs) have essential functions in the nervous system, including neuronal maturation, neurotransmission, synaptic plasticity, learning, and memory. However, reports regarding the roles of glutamate and NMDARs during early neuronal development are not available. Here, we present results showing that glutamate release and NMDARs regulate neuronal polarity acquisition. NMDARs loss- and gain-of-function antagonistically modulated neuronal polarization and axonal elongation. An intracellular mechanism involving Ca<sup>2+</sup> release from the endoplasmic reticulum, activation of the Rho GTPase Rac1, actin cytoskeleton rearrangements at the axonal growth cone, and H<sub>2</sub>O<sub>2</sub> production coupled these morphological changes. Optogenetic Rac1 activation simultaneously promoted lamellipodia formation and H<sub>2</sub>O<sub>2</sub> production suggesting functional coupling between these seemingly unconnected events. The mechanism presented here involves a dual function for the Rac1 protein that depends on glutamate and NMDAR activity. We propose that glutamate and NMDARs, via a complex set of signaling pathways, promote early neuronal development and axonal growth.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104027"},"PeriodicalIF":11.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962080","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 : 2026-01-13DOI: 10.1016/j.redox.2026.104025
Qian Liu , Binliang Liu , Zhenbao Liu , Lidan Gong , Min Li , Xiangjian Luo
Epstein–Barr virus (EBV)–associated carcinomas exhibit reprogrammed redox metabolism, yet the underlying regulatory network and potential metabolic vulnerabilities remain incompletely defined. Here we identify a viral–host transcriptional axis in which EBV EBNA1 induces the transcription factor FOSL2 to repress ALDH3A1. Restoration of ALDH3A1 in EBV-positive models disrupts NAD(P)H/NAD(P)+ homeostasis, inducing reductive stress. This reductive milieu upregulates GSNOR and TrxR1, potentiating the denitrosylation of GSK3β, leading to its stabilization and suppression of the Wnt/β-catenin pathway. We establish that S-nitrosylation at GSK3β Cys199 controls its stability, providing a mechanistic bridge from redox regulation to Wnt inhibition. Critically, ALDH3A1 elevation selectively curbs EBV-positive tumor growth, exploiting an infection-specific vulnerability in redox signaling. Thus, our findings integrate EBV-driven redox remodeling with Wnt/β-catenin signaling activation and propose ALDH3A1 induction as a promising therapeutic strategy for EBV-associated carcinomas.
{"title":"A viral–host redox axis: EBNA1–FOSL2–ALDH3A1 defines a targetable vulnerability in EBV-positive carcinomas","authors":"Qian Liu , Binliang Liu , Zhenbao Liu , Lidan Gong , Min Li , Xiangjian Luo","doi":"10.1016/j.redox.2026.104025","DOIUrl":"10.1016/j.redox.2026.104025","url":null,"abstract":"<div><div>Epstein–Barr virus (EBV)–associated carcinomas exhibit reprogrammed redox metabolism, yet the underlying regulatory network and potential metabolic vulnerabilities remain incompletely defined. Here we identify a viral–host transcriptional axis in which EBV EBNA1 induces the transcription factor FOSL2 to repress ALDH3A1. Restoration of ALDH3A1 in EBV-positive models disrupts NAD(P)H/NAD(P)<sup>+</sup> homeostasis, inducing reductive stress. This reductive milieu upregulates GSNOR and TrxR1, potentiating the denitrosylation of GSK3β, leading to its stabilization and suppression of the Wnt/β-catenin pathway. We establish that S-nitrosylation at GSK3β Cys199 controls its stability, providing a mechanistic bridge from redox regulation to Wnt inhibition. Critically, ALDH3A1 elevation selectively curbs EBV-positive tumor growth, exploiting an infection-specific vulnerability in redox signaling. Thus, our findings integrate EBV-driven redox remodeling with Wnt/β-catenin signaling activation and propose ALDH3A1 induction as a promising therapeutic strategy for EBV-associated carcinomas.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104025"},"PeriodicalIF":11.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962519","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 : 2026-01-13DOI: 10.1016/j.redox.2026.104030
Xv-shen Ding , Bao Wang , Zheng Han , Chen-xi Feng , Yang-ni Li , Yu-fei Wang , Jian-cai Guru , Jie Cao , Rui-li Zhang , Xue-lian Wang , Qian Yang , Yan Qu , Li Gao
Mitochondrial dysfunction and ferroptosis have emerged as pivotal contributors to dopaminergic (DA) neuron degeneration in Parkinson's disease (PD). Here, a previously unrecognized SIRT3–ACSS2–OPA1 axis that couples mitochondrial acetyl-CoA (Ac-CoA) metabolism to ferroptosis resistance is identified. Analysis of public human substantia nigra datasets reveals marked reduction in SIRT3 expression, which is further confirmed in 6-OHDA-induced PD models. To establish translational significance, analyses of serum and peripheral blood mononuclear cells (PBMCs) from PD patient cohort demonstrates decreased SIRT3 protein levels and deacetylase activity. Moreover, SIRT3 overexpression inhibits ferroptosis and mitochondrial fragmentation in neurons. Mechanistically, SIRT3 deacetylates and activates acetyl-CoA synthetase 2 (ACSS2), thereby facilitating the redistribution of Ac-CoA from mitochondria to the nucleus, leading to Optic atrophy 1 (OPA1) deacetylation. Meanwhile, this Ac-CoA reprogramming enhances histone H3K27 acetylation at the OPA1 promoter, and thereby drives OPA1 transcriptional upregulation. OPA1 restores mitochondrial homeostasis, alleviates iron accumulation, reduces lipid peroxidation, and ultimately suppresses ferroptosis. In vivo, pharmacological activation of SIRT3 or AAV-mediated Opa1 overexpression mitigates ferroptosis, preserves DA neurons, and improves motor performance in PD mice. This study uncovers mitochondrial Ac-CoA reprogramming as a key defense mechanism against ferroptosis, positioning the SIRT3–ACSS2–OPA1 pathway as a promising therapeutic target for PD.
{"title":"Mitochondrial acetyl-CoA reprogramming by the SIRT3–ACSS2–OPA1 axis confers resistance to ferroptosis in Parkinson's disease","authors":"Xv-shen Ding , Bao Wang , Zheng Han , Chen-xi Feng , Yang-ni Li , Yu-fei Wang , Jian-cai Guru , Jie Cao , Rui-li Zhang , Xue-lian Wang , Qian Yang , Yan Qu , Li Gao","doi":"10.1016/j.redox.2026.104030","DOIUrl":"10.1016/j.redox.2026.104030","url":null,"abstract":"<div><div>Mitochondrial dysfunction and ferroptosis have emerged as pivotal contributors to dopaminergic (DA) neuron degeneration in Parkinson's disease (PD). Here, a previously unrecognized SIRT3–ACSS2–OPA1 axis that couples mitochondrial acetyl-CoA (Ac-CoA) metabolism to ferroptosis resistance is identified. Analysis of public human substantia nigra datasets reveals marked reduction in <em>SIRT3</em> expression, which is further confirmed in 6-OHDA-induced PD models. To establish translational significance, analyses of serum and peripheral blood mononuclear cells (PBMCs) from PD patient cohort demonstrates decreased SIRT3 protein levels and deacetylase activity. Moreover, <em>SIRT3</em> overexpression inhibits ferroptosis and mitochondrial fragmentation in neurons. Mechanistically, SIRT3 deacetylates and activates acetyl-CoA synthetase 2 (ACSS2), thereby facilitating the redistribution of Ac-CoA from mitochondria to the nucleus, leading to Optic atrophy 1 (OPA1) deacetylation. Meanwhile, this Ac-CoA reprogramming enhances histone H3K27 acetylation at the <em>OPA1</em> promoter, and thereby drives OPA1 transcriptional upregulation. OPA1 restores mitochondrial homeostasis, alleviates iron accumulation, reduces lipid peroxidation, and ultimately suppresses ferroptosis. In vivo, pharmacological activation of SIRT3 or AAV-mediated <em>Opa1</em> overexpression mitigates ferroptosis, preserves DA neurons, and improves motor performance in PD mice. This study uncovers mitochondrial Ac-CoA reprogramming as a key defense mechanism against ferroptosis, positioning the SIRT3–ACSS2–OPA1 pathway as a promising therapeutic target for PD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104030"},"PeriodicalIF":11.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962079","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 : 2026-01-12DOI: 10.1016/j.redox.2026.104016
Jiaojiao Sun , Bo Xu , Yijing Chen , Meng Sui , Mochi Wang , Ranming Ma , Jinbo Wu , Shiyong Teng , Qingfeng Pang , Chunxiao Hu
Mitochondrial dysfunction during lung ischemia-reperfusion injury (LIRI) contributes to organ dysfunction. Aconitase-2 (ACO2), by enhancing the mitochondrial tricarboxylic acid (TCA) cycle in pulmonary vascular endothelial cells (PVECs), plays a critical role in maintaining cellular energy metabolic homeostasis. Single-cell RNA sequencing was performed to characterize cellular phenotypes within the lung tissue microenvironment of I/R mice, and bulk RNA sequencing was applied to identify differentially expressed genes associated with LIRI. Our clinical cohort included 65 healthy donors and 48 patients with LIRI to evaluate the correlation between serum ACO2 levels and lung function. In vivo, using a murine I/R model, we administered an adeno-associated virus for lung-specific ACO2 overexpression, as well as an ACO2 inhibitor (tricarballylic acid), to assess their effects on lung injury. In vitro, primary PVECs were isolated and subjected to hypoxia/reoxygenation (H/R), followed by ACO2 overexpression or knockout, and treatment with the ACO2 downstream metabolite derivative 4-octyl itaconate (4-OI), to investigate its role in mitochondrial function and apoptosis. Serum ACO2 levels were reduced in LIRI patients and exhibited a significant negative correlation with impaired lung function. In I/R mice, ACO2 overexpression ameliorated mitochondrial dysfunction and attenuated lung injury, whereas ACO2 inhibition exacerbated these pathological changes. In PVECs, ACO2 overexpression enhanced mitochondrial function and reduced apoptosis; conversely, ACO2 knockout exerted opposing effects. Notably, supplementation with 4-OI mitigated mitochondrial dysfunction and cellular apoptosis induced by ACO2 deficiency. These findings suggest that ACO2 has therapeutic potential in improving mitochondrial function, reducing apoptosis, and alleviating LIRI, positioning it as a promising target for the treatment of this condition.
{"title":"Unveiling a novel function of Aconitase-2: attenuating lung ischemia-reperfusion injury via inhibition of pulmonary endothelial apoptosis","authors":"Jiaojiao Sun , Bo Xu , Yijing Chen , Meng Sui , Mochi Wang , Ranming Ma , Jinbo Wu , Shiyong Teng , Qingfeng Pang , Chunxiao Hu","doi":"10.1016/j.redox.2026.104016","DOIUrl":"10.1016/j.redox.2026.104016","url":null,"abstract":"<div><div>Mitochondrial dysfunction during lung ischemia-reperfusion injury (LIRI) contributes to organ dysfunction. Aconitase-2 (ACO2), by enhancing the mitochondrial tricarboxylic acid (TCA) cycle in pulmonary vascular endothelial cells (PVECs), plays a critical role in maintaining cellular energy metabolic homeostasis. Single-cell RNA sequencing was performed to characterize cellular phenotypes within the lung tissue microenvironment of I/R mice, and bulk RNA sequencing was applied to identify differentially expressed genes associated with LIRI. Our clinical cohort included 65 healthy donors and 48 patients with LIRI to evaluate the correlation between serum ACO2 levels and lung function. In vivo, using a murine I/R model, we administered an adeno-associated virus for lung-specific ACO2 overexpression, as well as an ACO2 inhibitor (tricarballylic acid), to assess their effects on lung injury. In vitro, primary PVECs were isolated and subjected to hypoxia/reoxygenation (H/R), followed by ACO2 overexpression or knockout, and treatment with the ACO2 downstream metabolite derivative 4-octyl itaconate (4-OI), to investigate its role in mitochondrial function and apoptosis. Serum ACO2 levels were reduced in LIRI patients and exhibited a significant negative correlation with impaired lung function. In I/R mice, ACO2 overexpression ameliorated mitochondrial dysfunction and attenuated lung injury, whereas ACO2 inhibition exacerbated these pathological changes. In PVECs, ACO2 overexpression enhanced mitochondrial function and reduced apoptosis; conversely, ACO2 knockout exerted opposing effects. Notably, supplementation with 4-OI mitigated mitochondrial dysfunction and cellular apoptosis induced by ACO2 deficiency. These findings suggest that ACO2 has therapeutic potential in improving mitochondrial function, reducing apoptosis, and alleviating LIRI, positioning it as a promising target for the treatment of this condition.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104016"},"PeriodicalIF":11.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957331","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 : 2026-01-12DOI: 10.1016/j.redox.2026.104014
Yanting Zhou , Yuheng Zou , Xiao Zhong , Hongyan Li , Jingyi Yang , Hui Meng , Weiyao Xie , Pan Yao , Xiaoai Wu , Huawei Cai , Lin Li , Changning Wang , Wei Zhang , Ping Bai
Histone deacetylase 6 (HDAC6) represents a compelling target in major depressive disorder (MDD) pathophysiology, yet in vivo investigation has been constrained by inadequate imaging capabilities. Here, we report the development and validation of [18F]PB200, a novel positron emission tomography (PET) radiotracer specifically targeting brain HDAC6. PB200 was engineered with nanomolar affinity, high HDAC6 selectivity, and excellent blood-brain barrier permeability. [18F]PB200 was successfully synthesized in a radiochemical yield of 13 ± 4 % and validated through in vitro autoradiography and in vivo PET imaging across rodent and non-human primate models. We subsequently employed [18F]PB200 alongside TSPO-targeted [18F]FEPPA PET imaging in a chronic unpredictable mild stress (CUMS) mouse model of depression. This dual-tracer approach, complemented by in vitro experiments, revealed significant HDAC6 upregulation occurring concurrently with enhanced neuroinflammatory markers, including microglial activation and elevated pro-inflammatory cytokines. Our findings provide the first in vivo molecular imaging evidence directly linking HDAC6 upregulation to depressive pathophysiology and associated neuroinflammation. This work illuminates the molecular relationship between depression and neuroinflammation while establishing [18F]PB200 as a valuable tool for evaluating HDAC6-targeted therapeutic interventions, potentially advancing precision diagnosis and treatment approaches for depression.
{"title":"Development of a novel HDAC6 PET imaging agent uncovers associations between HDAC6 overexpression and neuroinflammation in depression","authors":"Yanting Zhou , Yuheng Zou , Xiao Zhong , Hongyan Li , Jingyi Yang , Hui Meng , Weiyao Xie , Pan Yao , Xiaoai Wu , Huawei Cai , Lin Li , Changning Wang , Wei Zhang , Ping Bai","doi":"10.1016/j.redox.2026.104014","DOIUrl":"10.1016/j.redox.2026.104014","url":null,"abstract":"<div><div>Histone deacetylase 6 (HDAC6) represents a compelling target in major depressive disorder (MDD) pathophysiology, yet <em>in vivo</em> investigation has been constrained by inadequate imaging capabilities. Here, we report the development and validation of [<sup>18</sup>F]PB200, a novel positron emission tomography (PET) radiotracer specifically targeting brain HDAC6. PB200 was engineered with nanomolar affinity, high HDAC6 selectivity, and excellent blood-brain barrier permeability. [<sup>18</sup>F]PB200 was successfully synthesized in a radiochemical yield of 13 ± 4 % and validated through <em>in vitro</em> autoradiography and <em>in vivo</em> PET imaging across rodent and non-human primate models. We subsequently employed [<sup>18</sup>F]PB200 alongside TSPO-targeted [<sup>18</sup>F]FEPPA PET imaging in a chronic unpredictable mild stress (CUMS) mouse model of depression. This dual-tracer approach, complemented by <em>in vitro</em> experiments, revealed significant HDAC6 upregulation occurring concurrently with enhanced neuroinflammatory markers, including microglial activation and elevated pro-inflammatory cytokines. Our findings provide the first <em>in vivo</em> molecular imaging evidence directly linking HDAC6 upregulation to depressive pathophysiology and associated neuroinflammation. This work illuminates the molecular relationship between depression and neuroinflammation while establishing [<sup>18</sup>F]PB200 as a valuable tool for evaluating HDAC6-targeted therapeutic interventions, potentially advancing precision diagnosis and treatment approaches for depression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104014"},"PeriodicalIF":11.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957333","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 : 2026-01-12DOI: 10.1016/j.redox.2026.104023
Anna Gremme , Emely Gerisch , Dominik Wieland , Julia Hillebrand , Franziska Drews , Marcello Pirritano , Ann-Kathrin Weishaupt , Janina Fuss , Vera Schwantes , Johannes Scholz , Vivien Michaelis , Alicia Thiel , Gawain McColl , Bernhard Michalke , Martin Simon , Heiko Hayen , Julia Bornhorst
Although the redox active essential trace element iron (Fe) is involved in many important biological processes, an overexposure can lead to the excessive formation of reactive oxygen and nitrogen species (RONS). Thus, total Fe accumulation, as for example observed in neurodegenerative diseases or diseases as hemochromatosis, can lead to adverse consequences, especially if the antioxidant system is weakened. This system, and especially the most abundant antioxidant in organisms, glutathione (GSH), can be impaired by excess RONS levels, which is relevant during aging and in the context of neurodegenerative diseases. In this study, we demonstrate the consequences of Fe overdosing or/and GSH depletion in Caenorhabditis elegans (C. elegans) on Fe homeostasis, mitochondrial mass, phospho- and sphingolipidome, and on the neurotransmitter levels of acetylcholine, serotonin, dopamine, and γ-aminobutyric acid. In order to investigate this, we treated L4 nematodes with Fe(III) ammonium citrate (FAC) for 24 h or/and diethyl maleate (DEM) for 2 h or 24 h. While FAC treatment alone did not affect mitochondrial mass and cardiolipin content, it increased the amount of several lipid classes and the neurotransmitter acetylcholine. Treatment with DEM alone resulted in GSH depletion by 70 % and was associated with decreased mitochondrial mass and increased Fe(II), lipid, acetylcholine, and serotonin levels. Genes involved in GSH biosynthesis, Fe homeostasis, mitochondrial stress response, lipid biosynthesis, and neurotransmitter regulation are differentially expressed after DEM treatment. In addition, we were able to determine the GSH-DEM product in the nematode using HPLC-MS/MS. Although FAC treatment increased total Fe content in the nematode fivefold, the combined treatment with DEM showed no further effects compared to treatment with FAC or DEM alone. Together, these findings highlight the consequences of an impaired intracellular redox system on mitochondria, lipidome, and neurological endpoints, and identify several pathways, metabolites, and potential compensatory as well as long lasting effects.
{"title":"Consequences of iron exposure and glutathione depletion on redox balance, lipidome, and neurotransmission in C. elegans","authors":"Anna Gremme , Emely Gerisch , Dominik Wieland , Julia Hillebrand , Franziska Drews , Marcello Pirritano , Ann-Kathrin Weishaupt , Janina Fuss , Vera Schwantes , Johannes Scholz , Vivien Michaelis , Alicia Thiel , Gawain McColl , Bernhard Michalke , Martin Simon , Heiko Hayen , Julia Bornhorst","doi":"10.1016/j.redox.2026.104023","DOIUrl":"10.1016/j.redox.2026.104023","url":null,"abstract":"<div><div>Although the redox active essential trace element iron (Fe) is involved in many important biological processes, an overexposure can lead to the excessive formation of reactive oxygen and nitrogen species (RONS). Thus, total Fe accumulation, as for example observed in neurodegenerative diseases or diseases as hemochromatosis, can lead to adverse consequences, especially if the antioxidant system is weakened. This system, and especially the most abundant antioxidant in organisms, glutathione (GSH), can be impaired by excess RONS levels, which is relevant during aging and in the context of neurodegenerative diseases. In this study, we demonstrate the consequences of Fe overdosing or/and GSH depletion in <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) on Fe homeostasis, mitochondrial mass, phospho- and sphingolipidome, and on the neurotransmitter levels of acetylcholine, serotonin, dopamine, and γ-aminobutyric acid. In order to investigate this, we treated L4 nematodes with Fe(III) ammonium citrate (FAC) for 24 h or/and diethyl maleate (DEM) for 2 h or 24 h. While FAC treatment alone did not affect mitochondrial mass and cardiolipin content, it increased the amount of several lipid classes and the neurotransmitter acetylcholine. Treatment with DEM alone resulted in GSH depletion by 70 % and was associated with decreased mitochondrial mass and increased Fe(II), lipid, acetylcholine, and serotonin levels. Genes involved in GSH biosynthesis, Fe homeostasis, mitochondrial stress response, lipid biosynthesis, and neurotransmitter regulation are differentially expressed after DEM treatment. In addition, we were able to determine the GSH-DEM product in the nematode using HPLC-MS/MS. Although FAC treatment increased total Fe content in the nematode fivefold, the combined treatment with DEM showed no further effects compared to treatment with FAC or DEM alone. Together, these findings highlight the consequences of an impaired intracellular redox system on mitochondria, lipidome, and neurological endpoints, and identify several pathways, metabolites, and potential compensatory as well as long lasting effects.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104023"},"PeriodicalIF":11.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957330","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 : 2026-01-12DOI: 10.1016/j.redox.2026.104022
Boshen Yang , Yizhi Chen , Xinjie Zheng , Taixi Li , Kaifan Niu , Zhixiang Wang , Xuanhao Xu , Qiya Huang , Xingyun Wang , Yuan Fang , Wei Liu , Zhenwei Yu , Dianhui Wei , YuanKang Zhu , Xian Jin , Chengxing Shen
Background
Triclosan (TCS), a widely used environmental antimicrobial agent, is associated with cardiovascular risks such as coronary heart disease; however, its effect on post-myocardial infarction (MI) prognosis remains unclear. This study investigated whether TCS exacerbated post-MI outcomes and the underlying mechanisms, with the goal of identifying potential preventive strategies.
Methods
MI models were established using mice with left anterior descending coronary artery ligation, alongside hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and human AC16 cardiomyocytes. A comprehensive set of methodologies was employed, including RNA sequencing, echocardiography, Western blotting, co-immunoprecipitation, dual-luciferase reporter assays, molecular docking, quantitative real-time PCR, histological/immunofluorescence staining, and oxidative stress parameter analyses. Mechanistic investigations utilized Nur77 knockout mice, AAV9-based viral vectors targeting Nur77 and NTRK2, adenoviruses, plasmids, and small-molecule inhibitors/activators.
Results
Exposure to environmentally relevant TCS concentrations dose-dependently aggravated short- and long-term post-MI cardiac dysfunction and ventricular remodeling in both male and female mice. Mechanistically, TCS induced TRIM13-mediated K48-linked ubiquitination and proteasomal degradation of the nuclear receptor Nur77, leading to reduced transcription of NTRK2. Downregulated NTRK2 suppressed the AKT/mTOR/YY1 signaling cascade, ultimately decreasing PGC-1α expression and impairing mitochondrial function—specifically mitochondrial oxidative phosphorylation. This bioenergetic deficit triggered excessive reactive oxygen species (ROS) production, promoting lipid peroxidation and exacerbating cardiomyocyte ferroptosis, cellular senescence, and the senescence-associated secretory phenotype (SASP). These pathological effects collectively exacerbated acute post-MI injury and facilitated the progression of long-term ventricular remodeling. Validation in NRCMs and human AC16 cardiomyocytes confirmed conserved phenotypes and mechanisms. Pharmacological activation of PGC-1α with ZLN005 mitigated TCS-induced deterioration of short- and long-term post-MI cardiac function and attenuated ventricular remodeling.
Conclusions
TCS exacerbates post-MI injury by disrupting the Nur77/NTRK2/PGC-1α axis, triggering mitochondrial dysfunction-mediated ferroptosis and senescence in cardiomyocytes of both male and female mice. Pharmacological activation of PGC-1α represents a potential strategy to counteract TCS-induced adverse outcomes after MI.
{"title":"Triclosan exacerbates post-myocardial infarction injury via Nur77 ubiquitination: Linking NTRK2/PGC-1α-mediated mitochondrial dysfunction to senescence and ferroptosis","authors":"Boshen Yang , Yizhi Chen , Xinjie Zheng , Taixi Li , Kaifan Niu , Zhixiang Wang , Xuanhao Xu , Qiya Huang , Xingyun Wang , Yuan Fang , Wei Liu , Zhenwei Yu , Dianhui Wei , YuanKang Zhu , Xian Jin , Chengxing Shen","doi":"10.1016/j.redox.2026.104022","DOIUrl":"10.1016/j.redox.2026.104022","url":null,"abstract":"<div><h3>Background</h3><div>Triclosan (TCS), a widely used environmental antimicrobial agent, is associated with cardiovascular risks such as coronary heart disease; however, its effect on post-myocardial infarction (MI) prognosis remains unclear. This study investigated whether TCS exacerbated post-MI outcomes and the underlying mechanisms, with the goal of identifying potential preventive strategies.</div></div><div><h3>Methods</h3><div>MI models were established using mice with left anterior descending coronary artery ligation, alongside hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and human AC16 cardiomyocytes. A comprehensive set of methodologies was employed, including RNA sequencing, echocardiography, Western blotting, co-immunoprecipitation, dual-luciferase reporter assays, molecular docking, quantitative real-time PCR, histological/immunofluorescence staining, and oxidative stress parameter analyses. Mechanistic investigations utilized Nur77 knockout mice, AAV9-based viral vectors targeting Nur77 and NTRK2, adenoviruses, plasmids, and small-molecule inhibitors/activators.</div></div><div><h3>Results</h3><div>Exposure to environmentally relevant TCS concentrations dose-dependently aggravated short- and long-term post-MI cardiac dysfunction and ventricular remodeling in both male and female mice. Mechanistically, TCS induced TRIM13-mediated K48-linked ubiquitination and proteasomal degradation of the nuclear receptor Nur77, leading to reduced transcription of NTRK2. Downregulated NTRK2 suppressed the AKT/mTOR/YY1 signaling cascade, ultimately decreasing PGC-1α expression and impairing mitochondrial function—specifically mitochondrial oxidative phosphorylation. This bioenergetic deficit triggered excessive reactive oxygen species (ROS) production, promoting lipid peroxidation and exacerbating cardiomyocyte ferroptosis, cellular senescence, and the senescence-associated secretory phenotype (SASP). These pathological effects collectively exacerbated acute post-MI injury and facilitated the progression of long-term ventricular remodeling. Validation in NRCMs and human AC16 cardiomyocytes confirmed conserved phenotypes and mechanisms. Pharmacological activation of PGC-1α with ZLN005 mitigated TCS-induced deterioration of short- and long-term post-MI cardiac function and attenuated ventricular remodeling.</div></div><div><h3>Conclusions</h3><div>TCS exacerbates post-MI injury by disrupting the Nur77/NTRK2/PGC-1α axis, triggering mitochondrial dysfunction-mediated ferroptosis and senescence in cardiomyocytes of both male and female mice. Pharmacological activation of PGC-1α represents a potential strategy to counteract TCS-induced adverse outcomes after MI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104022"},"PeriodicalIF":11.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957332","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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