Redox Biology最新文献_第3页

The C3–C3aR axis drives rotenone-induced cognitive damage via synaptic engulfment, dark microglia and PANoptosis C3-C3aR轴通过突触吞噬、暗小胶质细胞和PANoptosis驱动鱼藤酮诱导的认知损伤

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-30 DOI: 10.1016/j.redox.2026.104062

Jianing Liu , Liyan Hou , Yu Ma , Lu Tian , Jau-Shyong Hong , Jie Zhao , Qingshan Wang

Cognitive impairment, a common non-motor symptom of Parkinson's disease (PD), is a key factor in reducing the life quality of patients, but its pathogenesis remains unclear. Recent studies highlighted the role of Complement C3 in regulating neuroinflammation and cognitive function. This study aimed to elucidate the mechanisms through which C3 contributed to PD-related cognitive dysfunction, using a rotenone-induced mouse model. Rotenone exposure led to pronounced upregulation of astrocytic C3, while C3 deficiency significantly ameliorated neurodegeneration and α-synuclein Ser129 phosphorylation, accompanied by marked improvements in cognitive performance. Notably, the expression of C3a receptor (C3aR) was elevated in both microglia and neurons, and inhibition of C3aR with SB290157 effectively mitigated neuronal injury and cognitive decline. Mechanistically, blockade of the C3–C3aR axis suppressed microglial activation, reduced aberrant phagocytosis and synaptic engulfment, and restored synaptic plasticity. Subsequently, dark microglia characterized by activation of PKR-PERK-eIF2α-ATF4 pathways and abnormal lipid metabolism and release were also mitigated by C3 deletion or C3aR inhibition. Furthermore, inhibition of the C3–C3aR axis restored blood–brain barrier integrity, decreased TUNEL-positive cell numbers, and suppressed the expression or activation of PANoptosis-related markers in rotenone-exposed mice. In vitro experiments revealed that C3–C3aR axis promoted PANoptosome formation and PANoptosis through z-DNA and ZBP-1 interaction via mitochondrial ROS. Collectively, our findings uncovered the C3–C3aR axis as a critical mediator linking neuroinflammation, abnormal synaptic pruning, dark microglia, BBB impairments and neuron PANoptosis to cognitive decline in PD, providing new mechanistic insights and a potential therapeutic target for combating PD-related cognitive impairment.

认知障碍是帕金森病（PD）常见的非运动症状，是降低患者生活质量的关键因素，但其发病机制尚不清楚。最近的研究强调了补体C3在调节神经炎症和认知功能中的作用。本研究旨在通过鱼藤酮诱导的小鼠模型阐明C3对pd相关认知功能障碍的作用机制。鱼藤酮暴露导致星形胶质细胞C3明显上调，而C3缺乏显著改善神经变性和α-突触核蛋白Ser129磷酸化，并伴有认知能力的显著改善。值得注意的是，C3a受体（C3aR）在小胶质细胞和神经元中的表达均升高，SB290157抑制C3aR可有效减轻神经元损伤和认知能力下降。机制上，C3-C3aR轴的阻断抑制了小胶质细胞的激活，减少了异常吞噬和突触吞噬，恢复了突触的可塑性。随后，以PKR-PERK-eIF2α-ATF4通路激活和脂质代谢和释放异常为特征的暗小胶质细胞也通过C3缺失或C3aR抑制得到缓解。此外，在鱼藤酮暴露的小鼠中，C3-C3aR轴的抑制恢复了血脑屏障的完整性，减少了tunel阳性细胞的数量，抑制了panoptoism相关标记物的表达或激活。体外实验表明，C3-C3aR轴通过线粒体ROS通过z-DNA和ZBP-1相互作用促进PANoptosome的形成和PANoptosis。总的来说，我们的研究结果揭示了C3-C3aR轴是连接神经炎症、突触异常修剪、暗小胶质细胞、血脑屏障损伤和神经元PANoptosis与PD认知能力下降的关键介质，为对抗PD相关认知障碍提供了新的机制见解和潜在的治疗靶点。

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引用次数: 0

Intergenerational and organ-specific alterations in mitochondrial DNA copy number following preconception irradiation 孕前照射后线粒体DNA拷贝数的代际和器官特异性改变

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-30 DOI: 10.1016/j.redox.2026.104054

Ryosuke Seino , Hisanori Fukunaga

Ionizing radiation, a potent inducer of redox stress, perturbs both nuclear and mitochondrial genomes, yet how such stress shapes mitochondrial inheritance across generations remains unclear. In this study, we examined intergenerational and organ-specific mitochondrial responses to parental X-ray irradiation in mice. Eight-week-old male and female C57BL/6N mice were exposed to 2 Gy of single whole-body X-ray irradiation before mating, generating paternal-, maternal-, and dual-irradiated lineages. In the parents, peripheral blood-derived mitochondrial DNA copy number (mtDNAcn) transiently increased one day after exposure, consistent with a rapid mitochondrial response to redox stress. In newborn offspring, mtDNAcn displayed clear organ- and parent-of-origin specificity: brain mtDNAcn decreased in paternal- and dual-irradiation lineages, heart mtDNAcn remained unchanged, and liver mtDNAcn showed the most pronounced depletion across all irradiated lineages. No significant inter-organ correlations in mtDNAcn were observed. All irradiated lineages exhibited increased body weight and increased liver weight at birth, with a significant positive association between these traits. Liver weight was negatively associated with hepatic mtDNAcn. Multiple regression analysis further showed that maternal pre-exposure mtDNAcn and offspring hepatic mtDNAcn independently predicted neonatal liver weight. Taken together, these findings demonstrate that preconception irradiation induces acute mitochondrial responses in parents and is associated with intergenerational, organ-specific mtDNAcn dysregulation that manifests as offspring birth outcomes. Parental irradiation perturbs organ-specific mitochondrial genome regulation and predisposes the next generation to altered growth-related traits.

电离辐射是氧化还原应激的一种有效诱导剂，可以扰乱细胞核和线粒体基因组，但这种应激如何影响线粒体的代际遗传仍不清楚。在这项研究中，我们研究了小鼠对亲代x射线照射的代际和器官特异性线粒体反应。8周龄的雄性和雌性C57BL/6N小鼠在交配前接受2 Gy的单次全身x射线照射，产生父系、母系和双照射谱系。在父母中，暴露后一天外周血源性线粒体DNA拷贝数（mtDNAcn）短暂增加，与线粒体对氧化还原应激的快速反应一致。在新生儿中，mtDNAcn显示出明确的器官和父母来源特异性：在父系和双辐照谱系中，脑mtDNAcn减少，心脏mtDNAcn保持不变，肝脏mtDNAcn在所有辐照谱系中都表现出最明显的消耗。mtDNAcn在各器官间无明显相关性。所有辐照谱系在出生时均表现出体重增加和肝脏重量增加，这些性状之间呈显著正相关。肝脏重量与mtDNAcn呈负相关。多元回归分析进一步表明，母体暴露前mtDNAcn和子代肝脏mtDNAcn独立预测新生儿肝脏重量。综上所述，这些发现表明，孕前照射可诱导父母急性线粒体反应，并与代际、器官特异性mtDNAcn失调有关，这种失调表现为后代的出生结果。亲本辐照干扰器官特异性线粒体基因组调控，使下一代易发生生长相关性状的改变。

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引用次数: 0

LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones LRRK2通过调节线粒体铜伴侣的氧化还原状态来控制COX的组装

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-28 DOI: 10.1016/j.redox.2026.104061

Tae Young Kim , Eun-Hae Jang , Yun-Hee Bae , Eun-Mi Hur , Byoung Dae Lee

Mitochondrial dysfunction is a common pathological hallmark of neurodegenerative diseases. In Parkinson's disease (PD), the most popular age-related movement disorder, the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is closely associated with mitochondrial energetic deficits, reflecting their exceptionally high metabolic demand. The electron transport chain (ETC), essential for ATP production, comprises multiple protein complexes that require coordinated assembly and redox-sensitive regulation. In this study, we identified LRRK2—the most common genetic contributor to both familial and sporadic PD—as a regulator of cytochrome c oxidase (COX), the terminal enzyme of the ETC, through its control of the redox status of mitochondrial copper chaperones. Expression of pathogenic LRRK2 G2019S mutant increased the proportion of reduced (Cu-deficient) forms of COX11 and SCO1, two chaperones essential for COX metalation, thereby impairing COX assembly and promoting ETC dysfunction. Within this regulatory hierarchy, COX19 functions as a downstream effector of LRRK2 and an upstream modulator of COX11 and SCO1 redox status. Moreover, LRRK2 and COX19 reciprocally regulate each other's expression and cooperatively disrupted COX biogenesis. In vivo, exogenous expression of COX19 via AAV gene delivery induced dopaminergic neurodegeneration and motor deficits, which were effectively rescued by pharmacological inhibition of LRRK2 kinase activity. Together, these findings define a positive feedback LRRK2–COX19 signaling axis that governs mitochondrial redox homeostasis and COX assembly, highlighting a promising therapeutic target for PD and related mitochondrial disorders.

线粒体功能障碍是神经退行性疾病的常见病理标志。在帕金森病（PD）中，最常见的与年龄相关的运动障碍，黑质致密部（SNpc）中多巴胺能神经元的进行性丧失与线粒体能量缺陷密切相关，反映了它们异常高的代谢需求。电子传递链（ETC）对ATP的产生至关重要，由多个蛋白质复合物组成，需要协调组装和氧化还原敏感调节。在这项研究中，我们发现lrrk2 -家族性和散发性pd的最常见遗传贡献者-通过控制线粒体铜伴侣的氧化还原状态，作为ETC末端酶细胞色素c氧化酶（COX）的调节剂。致病性LRRK2 G2019S突变体的表达增加了COX金属化所必需的两种伴侣蛋白COX11和SCO1的减少（缺铜）形式的比例，从而损害COX组装并促进ETC功能障碍。在这一调控体系中，COX19作为LRRK2的下游效应体和COX11和SCO1氧化还原状态的上游调节剂。此外，LRRK2和COX19相互调节彼此的表达，并协同破坏COX的生物发生。在体内，通过AAV基因传递外源性表达COX19可诱导多巴胺能神经变性和运动障碍，通过药物抑制LRRK2激酶活性可有效挽救这些神经变性和运动障碍。总之，这些发现定义了一个控制线粒体氧化还原稳态和COX组装的正反馈lrrk2 - COX信号轴，突出了PD和相关线粒体疾病的有希望的治疗靶点。

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引用次数: 0

Cross-tissue deep profiling of redox proteome in obese mice using enhanced resin-assisted capture and data-independent acquisition 使用增强树脂辅助捕获和数据独立获取的肥胖小鼠氧化还原蛋白质组的跨组织深度分析

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-28 DOI: 10.1016/j.redox.2026.104056

Jiyuan Liu , Xinbo Jiang , Yunyu Li , Liye Shen , Xiaoliang Li , Xiaohui Wang , Jinlong Wang

Cysteine thiol modification plays a critical role in the precise regulation of the cellular redox state. Existing redox proteomic methodologies are often limited by their efficiency, complexity, and cost. To overcome these limitations, we developed and synthesized a series of novel enrichment resins. Three of these resins demonstrated a markedly enhanced enrichment efficiency. The application of one such resin, coupled with data-independent acquisition, allowed the systematic and reproducible quantification and analysis of thiol sites on a large scale within a single experiment. We further employed this strategy in a murine model of obesity and identified over 40,000 thiol sites across five tissues. These findings highlight the resin's capability to identify and quantify a significant number of thiol sites, offering a valuable resource for comprehensive investigations into redox regulation and oxidative stress in obesity.

半胱氨酸巯基修饰在细胞氧化还原状态的精确调控中起着至关重要的作用。现有的氧化还原蛋白质组学方法常常受到效率、复杂性和成本的限制。为了克服这些限制，我们开发并合成了一系列新的富集树脂。其中三种树脂的富集效率显著提高。一种这样的树脂的应用，加上数据独立的采集，允许在单个实验中大规模地对硫醇位点进行系统和可重复的量化和分析。我们进一步在小鼠肥胖模型中采用了这一策略，并在五个组织中确定了超过40,000个硫醇位点。这些发现突出了树脂识别和量化大量硫醇位点的能力，为全面研究肥胖中的氧化还原调节和氧化应激提供了宝贵的资源。

引用次数: 0

S-nitrosylation of HINT1 in macrophages aggravates foam cell formation and atherosclerosis 巨噬细胞中HINT1的s -亚硝基化加重泡沫细胞形成和动脉粥样硬化

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-28 DOI: 10.1016/j.redox.2026.104063

Ke Tang , Tianshu Zheng , Hao Zhu , Fan Xu , Congcong Ma , Zhenhua Qi , Siyi Cao , Qiang Da , Ke Yan , Wencheng Wu , Yi Han , Liping Xie , Yan Zhang , Yong Ji

Atherosclerosis (AS) is the primary cause of most cardiovascular diseases, such as coronary artery disease (CAD), myocardial infarctions and strokes. S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular diseases. Histidine triad nucleotide-binding protein 1 (HINT1) was identified S-nitrosylated at cysteine 84 (Cys84) in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages. S-nitrosylation of HINT1 (SNO-HINT1) in macrophages exacerbates lipid uptake and foam cell formation through upregulating SR-A1 and CD36. Furthermore, SNO-HINT1 was determined to inhibit degradation of SR-A1 mediated by lysosome pathway and promote CD36 transcription mediated by USF2. Mechanistically, comparing to unmodified HINT1, S-nitrosylation of HINT1 drives its CRM1 dependent nuclear export, which resulted in its more interaction with SR-A1 in cytoplasm and less interaction with USF2 in nucleus. Furthermore, inducible nitric oxide synthase (iNOS) was demonstrated as the enzyme that mediates the S-nitrosylation of HINT1. SNO-HINT1 was demonstrated to drive the development of atherosclerosis in LDLR^−/− mice fed with high fat diet. Overall, SNO-HINT1 drives foam cell formation and atherosclerosis through reducing degradation of SR-A1 mediated by lysosome pathway and promoting CD36 transcription mediated by USF2. Our findings suggest that SNO-HINT1 can be a potential therapeutic target for atherosclerosis.

动脉粥样硬化（AS）是大多数心血管疾病的主要原因，如冠状动脉疾病（CAD）、心肌梗死和中风。s -亚硝基化（SNO）是一种典型的基于氧化还原的翻译后修饰，与心血管疾病有关。在氧化低密度脂蛋白（ox-LDL）刺激的巨噬细胞中鉴定出组氨酸三核苷酸结合蛋白1 （HINT1）在半胱氨酸84 （Cys84）上s -亚硝基化。巨噬细胞中HINT1的s -亚硝基化（SNO-HINT1）通过上调SR-A1和CD36加剧脂质摄取和泡沫细胞形成。此外，SNO-HINT1抑制溶酶体途径介导的SR-A1降解，促进USF2介导的CD36转录。机制上，与未修饰的HINT1相比，HINT1的s -亚硝基化驱动其依赖CRM1的核输出，导致其与细胞质中SR-A1的相互作用增加，与细胞核中USF2的相互作用减少。此外，诱导型一氧化氮合酶（iNOS）被证实是介导HINT1 s -亚硝基化的酶。SNO-HINT1被证明可以促进高脂饲料喂养的LDLR - / -小鼠动脉粥样硬化的发展。总的来说，SNO-HINT1通过减少溶酶体途径介导的SR-A1降解和促进USF2介导的CD36转录来驱动泡沫细胞形成和动脉粥样硬化。我们的研究结果表明，SNO-HINT1可能是动脉粥样硬化的潜在治疗靶点。

{"title":"S-nitrosylation of HINT1 in macrophages aggravates foam cell formation and atherosclerosis","authors":"Ke Tang , Tianshu Zheng , Hao Zhu , Fan Xu , Congcong Ma , Zhenhua Qi , Siyi Cao , Qiang Da , Ke Yan , Wencheng Wu , Yi Han , Liping Xie , Yan Zhang , Yong Ji","doi":"10.1016/j.redox.2026.104063","DOIUrl":"10.1016/j.redox.2026.104063","url":null,"abstract":"<div><div>Atherosclerosis (AS) is the primary cause of most cardiovascular diseases, such as coronary artery disease (CAD), myocardial infarctions and strokes. S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular diseases. Histidine triad nucleotide-binding protein 1 (HINT1) was identified S-nitrosylated at cysteine 84 (Cys84) in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages. S-nitrosylation of HINT1 (SNO-HINT1) in macrophages exacerbates lipid uptake and foam cell formation through upregulating SR-A1 and CD36. Furthermore, SNO-HINT1 was determined to inhibit degradation of SR-A1 mediated by lysosome pathway and promote CD36 transcription mediated by USF2. Mechanistically, comparing to unmodified HINT1, S-nitrosylation of HINT1 drives its CRM1 dependent nuclear export, which resulted in its more interaction with SR-A1 in cytoplasm and less interaction with USF2 in nucleus. Furthermore, inducible nitric oxide synthase (iNOS) was demonstrated as the enzyme that mediates the S-nitrosylation of HINT1. SNO-HINT1 was demonstrated to drive the development of atherosclerosis in LDLR<sup>−/−</sup> mice fed with high fat diet. Overall, SNO-HINT1 drives foam cell formation and atherosclerosis through reducing degradation of SR-A1 mediated by lysosome pathway and promoting CD36 transcription mediated by USF2. Our findings suggest that SNO-HINT1 can be a potential therapeutic target for atherosclerosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104063"},"PeriodicalIF":11.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072058","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}

引用次数: 0

Small molecule HCY-NBD stabilizes GSTM2 via cys174 sulfenylation to attenuate high glucose induced endothelial cell senescence and calcification 小分子HCY-NBD通过cys174磺化作用稳定GSTM2，减轻高糖诱导的内皮细胞衰老和钙化

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-27 DOI: 10.1016/j.redox.2026.104058

Yangyang Zhang , Xinyu Dong , Xiaomeng Yan , Congyao Zhao , Xiaohui Chi , Baoxiang Zhao , Junying Miao , Fanzhen Hong , Zhaomin Lin

Exogenous Glutathione S-transferase Mu 2 (GSTM2) supplementation has emerged as a promising strategy to counteract aging. However, approaches to enhance endogenous GSTM2 expression remain underexplored. Here, we identify HCY-NBD, an SO₂-targeting small molecular that binds GSTM2 and stabilizes GSTM2 protein levels under high-glucose (HG)-induced vascular endothelial senescence. Mechanistically, HCY-NBD promotes sulfenylation at Cys174 of GSTM2 and inhibits its K48-linked ubiquitination at this residue, thereby stabilizing GSTM2 protein. In cellular studies, we observe that HCY-NBD upregulates GSTM2 and inhibits HG-induced senescence and calcification in vascular endothelial cells. Consistent with this, in vivo administration of HCY-NBD in db/db mice increases GSTM2 levels and mitigates senescence and calcification in the thoracic aorta. Collectively, our findings demonstrate that HCY-NBD inhibits HG-induced vascular senescence and calcification by stabilizing GSTM2 protein levels via enhancing Cys174 sulfenylation and suppression of site-specific ubiquitination-mediated degradation. Here, we first develop a new strategy to enhance endogenous GSTM2 and provide a novel therapeutic strategy for the prevention and treatment of vascular aging.

补充外源性谷胱甘肽s -转移酶Mu 2 （GSTM2）已成为对抗衰老的有希望的策略。然而，增强内源性GSTM2表达的方法仍未得到充分探索。在这里，我们发现了HCY-NBD，一个so2靶向小分子，结合GSTM2并稳定GSTM2蛋白水平在高糖（HG）诱导的血管内皮衰老。机制上，HCY-NBD促进GSTM2在Cys174位点的磺化，并抑制其在该残基上的k48连锁泛素化，从而稳定GSTM2蛋白。在细胞研究中，我们观察到HCY-NBD上调GSTM2，抑制hg诱导的血管内皮细胞衰老和钙化。与此一致的是，在db/db小鼠体内给予HCY-NBD可增加GSTM2水平，减轻胸主动脉的衰老和钙化。总之，我们的研究结果表明，HCY-NBD通过增强Cys174磺化和抑制位点特异性泛素化介导的降解来稳定GSTM2蛋白水平，从而抑制hg诱导的血管衰老和钙化。本研究首先开发了一种增强内源性GSTM2的新策略，为预防和治疗血管衰老提供了一种新的治疗策略。

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引用次数: 0

Patient-derived lung organoids from bronchoalveolar lavage capture epithelial heterogeneity and disease biology in bronchopulmonary dysplasia 支气管肺发育不良患者来源于支气管肺泡灌洗的肺类器官捕获上皮异质性和疾病生物学

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-27 DOI: 10.1016/j.redox.2026.104057

Shilpa Sonti , Abiud Cantu , Manuel Cantu Guttierez , Connor Leek , Phinzy Pelton , Erik A. Jensen , Krithika Lingappan

Modeling neonatal lung disease ex vivo to elucidate disease pathogenesis is particularly challenging. We hypothesized that airway organoids derived from bronchoalveolar lavage (BAL) samples obtained from intubated preterm infants with bronchopulmonary dysplasia (BPD) will recapitulate the epithelial heterogeneity seen in human airways and can be used to study lung injury and therapeutic responses. Here, we demonstrate that BAL sample-derived airway organoids from ventilator-dependent patients with established BPD exhibited cellular heterogeneity consistent with that observed in the human airway. Developed organoids contain basal cell progenitors and a spectrum of differentiated epithelial subtypes, including secretory, ciliated, PNECs, and hillock cells. Hyperoxia exposure and treatment with dexamethasone caused significant cellular transcriptional changes and highlighted biological pathways, both known and novel, with distinct findings based on sex as a biological variable. Findings were validated in an independent dataset from human BPD lung samples. Infant BAL-derived human lung organoids represent a cutting-edge model that bridges a critical gap in BPD research. They combine the advantages of being patient-specific and capturing developmental lung biology, with the experimental flexibility of an in vitro system.

体外模拟新生儿肺部疾病以阐明疾病发病机制尤其具有挑战性。我们假设，从支气管肺发育不良（BPD）插管早产儿的支气管肺泡灌洗（BAL）样本中提取的气道类器官将概括人类气道中所见的上皮异质性，并可用于研究肺损伤和治疗反应。在这里，我们证明来自呼吸机依赖患者的BAL样本衍生的气道类器官与在人类气道中观察到的细胞异质性一致。发育的类器官包含基底细胞祖细胞和一系列分化的上皮亚型，包括分泌细胞、纤毛细胞、pnec细胞和丘状细胞。高氧暴露和地塞米松治疗引起了显著的细胞转录变化和突出的生物学途径，无论是已知的还是新的，基于性别作为生物学变量的不同发现。研究结果在来自人类BPD肺样本的独立数据集中得到了验证。婴儿bal衍生的人类肺类器官代表了一个前沿模型，填补了BPD研究的关键空白。它们结合了患者特异性和捕获发育性肺生物学的优势，以及体外系统的实验灵活性。

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引用次数: 0

Are glutathionylated aldehyde reductases the missing piece of the “catecholaldehyde hypothesis” in Parkinson's disease? A medical hypothesis concerning the detoxification of 4-hydroxynonenal (HNE) and 3,4-dihydroxyphenylacetaldehyde (DOPAL) 谷胱甘肽醛还原酶是帕金森病中“儿茶酚醛假说”缺失的部分吗？4-羟基壬烯醛（HNE）和3,4-二羟基苯乙醛（DOPAL）解毒的医学假说

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-27 DOI: 10.1016/j.redox.2026.104060

Rossella Rotondo , Marta Russo , Federico Iacovelli , Valeria Calabrese , Antonio de Iure , Maria Gaglione , Lorenza Leonardi , Gabriella Cocorocchia , Fabrizio Stocchi , Vilberto Stocchi , Maria Francesca de Pandis , Barbara Picconi

The autotoxicity of the monoamine oxidase (MAO) reaction product 3,4-dihydroxyphenylacetaldehyde (DOPAL) is central to the “catecholaldehyde hypothesis”, which posits that interactions between DOPAL and the protein α-synuclein contribute to the degeneration of catecholaminergic neurons in Parkinson's disease (PD). Dopamine (DA) can undergo spontaneous or enzymatic oxidation, generating dopamine-quinone (DA-Q) and DOPAL, respectively. While growing evidence highlights the quinonization of numerous proteins in catecholaminergic cells due to the high reactivity of DA-Q, the electrophilic properties of DOPAL and its quinone derivative (DOPAL-quinone, DOPAL-Q) have received less attention, along with potential detoxification pathways.

Here, we propose a refinement of the “catecholaldehyde hypothesis” by extending the detoxification machinery described for 3-glutathionyl-4-hydroxynonenal (GS-HNE) to the formation of glutathionylated DOPAL adducts. Conjugation of DOPAL-Q with glutathione (GSH) would generate 5-S-glutathionyl-3,4-dihydroxyphenylacetaldehyde (GS-DOPAL). Analogous to GS-HNE, the aldehyde group of GS-DOPAL could be reduced to 5-S-glutathionyl-3,4-dihydroxyphenylethanol (GS-DOPET) by glutathione-dependent aldehyde reductases such as aldose reductase (AKR1B1) and carbonyl reductase 1 (CBR1). Conversely, oxidation of the phenolic hydroxyl groups by CBR1 to yield 5-S-glutathionyl-3,4-dioxophenylacetaldehyde (GS-DOPAL-Q) may also occur. We suggest that the excretion of such GS-adducts via glutathione-electrophile transporters could open new perspectives for identifying early biomarkers of PD and for evaluating the disease-modifying potential of MAO inhibitors.

单胺氧化酶（MAO）反应产物3,4-二羟基苯乙醛（DOPAL）的自毒性是“儿茶酚醛假说”的核心，该假说认为DOPAL和蛋白质α-突触核蛋白之间的相互作用导致了帕金森病（PD）中儿茶酚胺能神经元的退化。多巴胺（DA）可以自发氧化或酶促氧化，分别生成多巴胺-醌（DA- q）和DOPAL。虽然越来越多的证据表明，由于DA-Q的高反应性，儿茶酚胺能细胞中许多蛋白质的醌化，但DOPAL及其醌衍生物（DOPAL-醌，DOPAL-q）的亲电性质以及潜在的解毒途径受到的关注较少。在这里，我们提出了一个细化的“儿茶酚假说”通过扩展解毒机制描述的3-谷胱甘肽-4-羟基壬烯醛（GS-HNE）的形成谷胱甘肽化DOPAL加合物。DOPAL-Q与谷胱甘肽（GSH）偶联可生成5- s -谷胱甘肽-3,4-二羟基苯乙醛（GS-DOPAL）。与GS-HNE类似，GS-DOPAL的醛基可以通过谷胱甘肽依赖的醛还原酶(如醛糖还原酶（AKR1B1）和羰基还原酶1 （CBR1）还原为5- s -谷胱甘肽-3,4-二羟基苯乙醇（GS-DOPET）。相反，酚羟基被CBR1氧化生成5- s -谷胱甘肽-3,4-二氧苯乙醛（GS-DOPAL-Q）也可能发生。我们认为，这些gs加合物通过谷胱甘肽亲电转运体的排泄可以为识别PD的早期生物标志物和评估MAO抑制剂的疾病改善潜力开辟新的视角。

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引用次数: 0

DMNQ induces ferroptosis and augments the efficacy of anti-PD-L1 immunotherapy in gastric cancer via the STAT3/SLC1A4 axis to mediate cysteine metabolism reprogramming DMNQ通过STAT3/SLC1A4轴介导半胱氨酸代谢重编程，诱导铁下垂，增强抗pd - l1免疫治疗胃癌的疗效

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-26 DOI: 10.1016/j.redox.2026.104055

Wenshuai Zhu , He Qi , Fubo Jing , Yuxuan Shi , Yuanxin Xing , Xiaoli Ma , Bin Ning , Yunshan Wang , Yanfei Jia

Ferroptosis plays an essential role in tumor progression. Therapeutic agents targeting ferroptosis emerge as a novel strategy for cancer treatment. Abnormal amino acid metabolism can control ferroptosis sensitivity in cancer cells, and lead to the deficiency or accumulation of specific products in the tumor microenvironment (TME). Here, we demonstrated that 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced growth inhibition in gastric cancer cell lines, primary gastric cancer mouse models, and patient-derived tumor organoids. DMNQ exerted ferroptosis inducing effects by inhibiting STAT3 phosphorylation and transcriptional activity. Importantly, the STAT3/SLC1A4 axis regulated cysteine uptake, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy. Collectively, our findings revealed a critical mechanism by which DMNQ exerts a significant anti-cancer role in gastric cancer through increasing ferroptosis to enhance cancer immunotherapy and may provide a novel therapeutic strategy for gastric cancer.

铁下垂在肿瘤进展中起重要作用。针对铁下垂的治疗药物成为癌症治疗的新策略。异常的氨基酸代谢可以控制癌细胞对铁下垂的敏感性，导致肿瘤微环境（tumor microenvironment， TME）中特定产物的缺乏或积累。在这里，我们证明了2,3-二甲氧基-1,4-萘醌（DMNQ）对胃癌细胞系、原发性胃癌小鼠模型和患者来源的肿瘤类器官的生长抑制作用。DMNQ通过抑制STAT3的磷酸化和转录活性来诱导铁下垂。重要的是，STAT3/SLC1A4轴调节半胱氨酸摄取、T细胞杀伤肿瘤和抗pd - l1免疫治疗的疗效。总之，我们的研究结果揭示了DMNQ通过增加铁下垂来增强癌症免疫治疗在胃癌中发挥重要抗癌作用的关键机制，并可能为胃癌的治疗提供新的治疗策略。

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引用次数: 0

XPR1 downregulation inhibits hepatocellular carcinoma progression by suppressing serine metabolism XPR1下调通过抑制丝氨酸代谢抑制肝细胞癌进展

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2026-01-26 DOI: 10.1016/j.redox.2026.104053

Zi-qiang Liao , Ze-ning Chen , Yang-feng Lv , Yuan-yuan Zhang , Zhi-xing Liu , Zhi-qiang Deng , Qing-rong Liang , Chun-bo Zhang , Qun Tang

Xenotropic and polytropic retrovirus receptor 1 (XPR1) is highly expressed in various tumors and is associated with poor clinical prognosis, making it a proposed therapeutic target for cancer. However, the mechanism of XPR1 in tumorigenesis, particularly in hepatocellular carcinoma (HCC), remains unclear. Emerging evidence suggests that the knockdown of XPR1 in HCC cells leads to redox imbalance and mitochondrial damage. In this study, we aimed to investigate the molecular mechanisms and novel biological functions of XPR1 in HCC. Our findings revealed that XPR1 knockdown downregulated PHGDH expression, resulting in reduced serine biosynthesis, compromised redox homeostasis, exacerbated DNA damage, and pronounced mitochondrial fragmentation. Importantly, we identified MNX1 as a transcription factor of PHGDH. Restoration of MNX1 or PHGDH expression in XPR1-knockdown HCC cells effectively restored redox homeostasis and rescued tumor progression-associated functions. Moreover, in HCC cells in which XPR1 was knocked down, the re-expression of PHGDH effectively restored the intracellular serine level and tumorigenic capacity in vivo. Taken together, the results of our study demonstrate that XPR1 knockdown in HCC disrupts MNX1-mediated regulation of PHGDH expression, impairing serine metabolism and inducing redox imbalance, ultimately suppressing HCC progression. These findings suggest that XPR1 may serve as a therapeutic target for HCC.

异向性和多向性逆转录病毒受体1 （Xenotropic and polytropic retrovirus receptor 1, XPR1）在多种肿瘤中高表达，且与临床预后不良相关，是一种被提出的治疗肿瘤的靶点。然而，XPR1在肿瘤发生中的机制，特别是在肝细胞癌（HCC）中的机制尚不清楚。新出现的证据表明，HCC细胞中XPR1的敲低导致氧化还原失衡和线粒体损伤。在本研究中，我们旨在探讨XPR1在HCC中的分子机制和新的生物学功能。我们的研究结果表明，XPR1敲低会下调PHGDH的表达，导致丝氨酸生物合成减少，氧化还原稳态受损，DNA损伤加剧，线粒体断裂。重要的是，我们发现MNX1是PHGDH的转录因子。在xpr1敲低的HCC细胞中，恢复MNX1或PHGDH的表达可以有效地恢复氧化还原稳态，并恢复肿瘤进展相关功能。此外，在XPR1被敲除的HCC细胞中，重新表达PHGDH可以有效地恢复细胞内丝氨酸水平和体内的致瘤能力。综上所述，我们的研究结果表明，在HCC中，XPR1敲低会破坏mnx1介导的PHGDH表达调节，损害丝氨酸代谢，诱导氧化还原失衡，最终抑制HCC进展。这些发现提示XPR1可能作为HCC的治疗靶点。

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