Redox Biology最新文献

{"title":"NDP52 deficiency accelerates chondrocyte degeneration through promoting pathogenic mitochondrial ROS via reverse electron transport","authors":"Yutao Zhu ,&nbsp;Yaohan Xu ,&nbsp;Dinqi Xie ,&nbsp;Nengfeng Yu ,&nbsp;Jiaxin Chen ,&nbsp;Jiechao Xia ,&nbsp;Zixuan Mei ,&nbsp;Yang Jin ,&nbsp;Chuan Hu ,&nbsp;Pan Tang ,&nbsp;Sicheng Jiang ,&nbsp;Chao Jiang ,&nbsp;Honghai Song ,&nbsp;Zhijun Hu","doi":"10.1016/j.redox.2025.103747","DOIUrl":"10.1016/j.redox.2025.103747","url":null,"abstract":"<div><div>NDP52, a constituent of the selective autophagy receptors (SARs), was recognized for its involvement in facilitating substrate degradation via autophagic bridging. However, its autonomous function apart from autophagy remained largely unexplored. Here, we reported that NDP52 was down-regulated in degenerated chondrocytes. Besides, NDP52 deficiency promoted the extracellular matrix (ECM) degradation, inflammation, cell apoptosis and senescence via its autophagy-independent functions. The absence of NDP52 disrupted the flow of electron respiration chains and led to the production of intracellular mitochondrial reactive oxygen species (mtROS). Subsequent mechanistic investigations revealed that the downregulation of NDP52 upregulated the expression levels of mitochondrial complex Ⅰ by modulating MTIF3 expression, leading to reverse electron transport (RET) and mtROS production. Our research highlights the significance of NDP52 in facilitating chondrocyte degeneration and osteoarthritis, and provides insights into the distinctive mechanism by which autophagy receptors NDP52 induce intracellular mitochondrial ROS dysregulation via non-canonical pathways.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103747"},"PeriodicalIF":10.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144557428","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}

{"title":"EMAP-II from macrophage-derived extracellular vesicles drives neutrophil extracellular traps formation via PI3K/AKT/mtROS in lung ischemia/reperfusion injury","authors":"Hanhong Zhuang ,&nbsp;Xuemei Song ,&nbsp;Jiemei Li ,&nbsp;Zhao Li ,&nbsp;Siyi Wu ,&nbsp;Peng Wang ,&nbsp;Honglei Shen ,&nbsp;Xiaojing He ,&nbsp;Youyuan Guo ,&nbsp;Zhiping Li ,&nbsp;Fei Lin","doi":"10.1016/j.redox.2025.103750","DOIUrl":"10.1016/j.redox.2025.103750","url":null,"abstract":"<div><div>Lung ischemia/reperfusion injury (LIRI) is a significant complication following lung transplantation driven by neutrophil extracellular traps (NETs) associated with mitochondrial oxidative stress. However, the intercellular signaling mechanisms mediating oxidative stress remain unresolved. Here, we elucidated a mitochondrial reactive oxygen species (mtROS) amplification mechanism driven by extracellular vesicles (EVs). In this mechanism, EVs derived from oxygen-glucose deprivation/reperfusion (OGD/R)-activated macrophages transferred endothelial monocyte-activating polypeptide-II (EMAP-II) to neutrophils, suppressed PI3K/AKT signaling, and thereby induced mitochondrial oxidative stress that drove pathological NETs formation. Proteomic profiling identified EMAP-II as a key signaling molecule enriched in EVs secreted by OGD/R-activated macrophages. Pharmacological inhibition of mtROS or AKT activation abolished NETs formation, confirming the PI3K/AKT/mtROS as the central redox-sensitive pathway. Crucially, shRNA-mediated EMAP-II knockdown in macrophages abolished the ability of OGD/R-EVs to induce mtROS and NETs formation, mitigating pulmonary inflammation and tissue injury in mice. This study establishes EMAP-II from macrophage-derived EVs as transcellular drivers of neutrophil mitochondrial oxidative stress. We propose EMAP-II blockade as a therapeutic strategy to disrupt the pathogenic cascade in LIRI, wherein macrophage-derived EVs trigger NETs formation through PI3K/AKT/mtROS.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103750"},"PeriodicalIF":10.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549128","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}

{"title":"Ascorbic acid deficiency promotes metabolic remodeling and pulmonary fibrosis that leads to respiratory failure in Sod1 and Akr1a double-knockout mice","authors":"Tsukasa Osaki ,&nbsp;Takujiro Homma ,&nbsp;Yuya Soma ,&nbsp;Satoshi Miyata ,&nbsp;Yumi Matsuda ,&nbsp;Junichi Fujii","doi":"10.1016/j.redox.2025.103749","DOIUrl":"10.1016/j.redox.2025.103749","url":null,"abstract":"<div><div>We recently reported that mice with a double knockout (DKO) of Sod1 encoding superoxide dismutase 1 (SOD1) and Akr1a encoding aldehyde reductase survived more than one year when supplemented with ascorbic acid (Asc) (1.5 mg/ml in drinking water), and that the withdrawal of Asc resulted in premature death in only two weeks due to oxidative damage-associated pneumonia. SOD1 is known to disable the radical electrons of superoxide, which suppresses the subsequent formation of highly reactive oxygen species (ROS). Akr1a encodes aldehyde reductase, which catalyzes the biosynthesis of Asc, which is a strong nutritional antioxidant. In this study, we sought to gain insight into the metabolic basis for the progression of respiratory failure in the DKO mice. Pathological examinations have revealed pulmonary damage and the progression of fibrosis caused by an elevation in pulmonary cell death in these mice. Metabolite analyses have shown that substrate compounds catabolized in the tricarboxylic acid cycle are shifted from carbohydrates to amino acids, which leads to polyamine synthesis. While proteins involved in cell polarization, adhesion, and transport are increased in the lungs, showing trends similar to those of activated leukocytes, antioxidative enzymes were characteristically decreased in the lungs. Carbonyl proteins were originally high in the DKO mice but did not increase following Asc withdrawal, which was likely caused by stimulation of the degradation of oxidized proteins through the ubiquitin-proteasome system. It is conceivable that the oxidative insult due to Asc insufficiency under Sod1 deficiency causes protein oxidation followed by degradation, which fuels the tricarboxylic acid cycle. Remodeling the metabolic pathways for amino acid use increases polyamine synthesis, which could stimulate pulmonary fibrosis and lead to respiratory failure.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103749"},"PeriodicalIF":10.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549080","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}

{"title":"A critical role for gastric xanthine oxidoreductase in the formation of S-nitrosothiols and blood pressure responses to nitrite in rats","authors":"Carla Fiama de Azevedo Medeiros ,&nbsp;Evandro Manoel Neto-Neves ,&nbsp;Indiara Vieira Santana ,&nbsp;Jéssica Maria Sanches-Lopes ,&nbsp;Renato Corrêa Nogueira ,&nbsp;Rose Inês Matos Batista ,&nbsp;Sandra Oliveira Conde-Tella ,&nbsp;Marcelo F. Montenegro ,&nbsp;Jose Eduardo Tanus-Santos","doi":"10.1016/j.redox.2025.103748","DOIUrl":"10.1016/j.redox.2025.103748","url":null,"abstract":"<div><div>Nitrite and nitrate bioactivation to nitric oxide (NO) in the enterosalivary cycle of nitrate offers an enormous therapeutic potential for cardiovascular and metabolic diseases and involves xanthine oxidoreductase (XOR), an enzyme widely expressed in the gastrointestinal system. XOR has nitrite reductase activity, reducing nitrite to NO, especially under low pH conditions. Here, we hypothesized that XOR activity critically interacts with acidic gastric pH to cause the blood pressure responses to oral nitrite. To test this hypothesis, rats pretreated with the XOR inhibitor allopurinol (100 mg/kg, by gavage, or vehicle) were treated with N⍵-nitro-<span>l</span>-arginine methyl ester; 60 mg/kg, i.v.) to induce acute hypertension, and received sodium nitrite (1, 5, and 15 mg/kg) in the stomach or in the duodenum. Mean arterial blood pressure (MAP) was monitored invasively. Ozone-based reductive chemiluminescence assays were performed to evaluate plasma nitrite, nitrate, total nitrosylated species and S-nitrosothiols (RSNO) concentrations. Gastric pH was assessed and XOR activity in the stomach and duodenum was assessed by fluorimetry. We found more profound MAP responses to nitrite administered in the duodenum than in the stomach. Importantly, XOR inhibition completely blunted nitrite-induced RSNO formation and hypotensive responses when nitrite is administered in the stomach, whereas XOR inhibition did not affect the responses when nitrite was administered in the duodenum, even though XOR activity is much higher in the duodenum than in the stomach. These results suggest a critical interaction between XOR activity and gastric acidity in mediating RSNO formation and the cardiovascular effects of oral nitrite. These results may help to design better oral nitrite therapeutic formulations.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103748"},"PeriodicalIF":10.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522907","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}

{"title":"USP10 protects against pressure overload-induced mitochondrial morphofunctional defects and pathological cardiac hypertrophy through stabilizing cytoplasmic Mfn2","authors":"Runjing Li, Feng Gao, Yunan Chen, Jiamin Zhao, Rui Shi, Man Li, Zhenzi Zuo, Pan Chang, Dema De, Lin Chen, Feng Fu, Mingge Ding","doi":"10.1016/j.redox.2025.103745","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103745","url":null,"abstract":"Increasing evidence has implicated the important role of mitochondrial morphofunctional defects in pathological myocardial hypertrophy and heart failure. Deubiquitinating enzymes (DUBs) are involved in protein stability maintenance and regulate multiple cellular processes, while it remains largely unclear whether DUBs participate in the maintenance of mitochondrial morphofunction. The aim of this study was to investigate the possible link between DUBs and abnormal mitochondrial morphofunction in pressure overload-induced pathological cardiac hypertrophy and explore the underlying molecular mechanism. RNA sequencing results showed that ubiquitin-mediated proteolysis was markedly enriched in pressure overload-induced hypertrophied and failing myocardium, and USP10 was identified as the most significantly downregulated gene among them and correlated with heart failure severity in human heart samples. Restoration of USP10 mitigates cardiac hypertrophy and dysfunction as well as abnormal mitochondrial morphofunction in vitro and in vivo. Immunoprecipitation and mass spectrometry analysis mechanistically revealed that USP10 directly interacted with Mfn2 (a mitochondrial outer membrane protein). Interestingly, the interaction between Mfn2 and USP10 occurred in cytoplasm but not on mitochondria. His-679 in the UCH domain of USP10 exerted deubiquitination to maintain the stability of the Mfn2 by removing the K11/K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining mitochondrial function and homeostasis. Knockdown or knockout of Mfn2 largely eliminated the cardioprotection of USP10. Additionally, reduced USP10 expression in hypertrophied myocardium was induced by impaired translation of Yy1. Together, our findings provide a USP10-modulated mitochondrial homeostasis mechanism that enhances the stability of cytoplasmic Mfn2 before its translocation to mitochondria. USP10 may represent a novel therapeutic target for combating pressure overstress-induced cardiac hypertrophy and heart failure.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"47 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515918","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}

{"title":"Anemoside B4 alleviates ulcerative colitis by attenuating intestinal oxidative stress and NLRP3 inflammasome via activating aryl hydrocarbon receptor through remodeling the gut microbiome and metabolites","authors":"Hao Wu ,&nbsp;Yao-lei Li ,&nbsp;Yu Wang ,&nbsp;Yu-ge Wang ,&nbsp;Jia-hui Hong ,&nbsp;Mi-mi Pang ,&nbsp;Pan-miao Liu ,&nbsp;Jian-jun Yang","doi":"10.1016/j.redox.2025.103746","DOIUrl":"10.1016/j.redox.2025.103746","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease of the intestines with a significant increase in global incidence in recent years. Oxidative stress and inflammation are two hallmarks of UC pathogenesis. Anemoside B4 (AB4), a pentacyclic triterpenoid saponin, exhibits significant antioxidant and anti-inflammatory properties and shows potential for preventing UC. Here, an animal model induced by dextran sodium sulfate (DSS) was used to investigate the effect of AB4 on UC. The results demonstrated that AB4 significantly reduces intestinal oxidative stress and inflammation in UC mice, while also protecting intestinal barrier function. Furthermore, AB4 helps restore intestinal microbial balance primarily by modulating the abundance of <em>Lactobacillus</em>, which enhances the metabolism of short-chain fatty acids and upregulates the production of butyric acid (BA). Pseudogerm-free mice and fecal microbiota transplantation (FMT) demonstrated that AB4 significantly mitigated UC in a gut microbe-dependent manner. Both AB4 and BA markedly activate the aromatic hydrocarbon receptor (AhR). The intestinal organoid results suggest BA may activate the AhR to inhibit ROS production and activation of NLRP3 inflammasome, thereby protecting intestinal integrity. Administration of AhR antagonists abolished the protective effects, thus confirming the involvement of AhR in the underlying mechanism. Overall, these results indicate that AB4 is an effective agent against UC mainly by activating the AhR through gut microbial short-chain fatty acid metabolites to inhibit intestinal oxidative stress and inflammation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103746"},"PeriodicalIF":10.7,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515942","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}

{"title":"Corrigendum to “Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson's disease model” [Redox Biol. 22 (2019): 101134]","authors":"Liyan Hou, Fuqiang Sun, Ruixue Huang, Wei Sun, Dan Zhang, Qingshan Wang","doi":"10.1016/j.redox.2025.103738","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103738","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"34 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515919","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}

{"title":"Acute stimulation of glucose metabolism by H2O2 sustains the NADPH steady-state under oxidative stress","authors":"C. Aburto ,&nbsp;I. Ruminot ,&nbsp;A. San Martín","doi":"10.1016/j.redox.2025.103740","DOIUrl":"10.1016/j.redox.2025.103740","url":null,"abstract":"<div><div>Oxidative stress reprograms metabolic flux from glycolysis to the pentose phosphate pathway. Recently, it has been proposed that NADPH acts as a key molecule in pentose phosphate pathway regulation by exerting negative feedback through tonic inhibition of glucose-6-phosphate dehydrogenase. Interestingly, recent studies show that NADPH levels remain stable during acute exposure to hydrogen peroxide in the presence of glucose, ruling out NADPH-dependent feedback inhibition. We hypothesize that hydrogen peroxide triggers a feedforward activation mechanism, increasing NADPH production even before any detectable NADPH depletion. To probe this hypothesis, we used a panel of genetically encoded fluorescent indicators to monitor glucose, NADPH, fructose 1,6-bisphosphate and pyruvate in single cells with high temporal resolution. Our results reveal that hydrogen peroxide rapidly activates glucose transport and consumption rates, enabling cells to preserve NADPH steady-state levels during early oxidative stress. Notably, this response precedes NADPH depletion, implying an anticipatory phenomenon that boosts NADPH production prior to its consumption. Furthermore, hydrogen peroxide induced an acute perturbation of fructose 1,6-bisphosphate steady-state and an increase of pyruvate accumulation. The pharmacological inhibition of the PPP’s gateway enzymes, glucose-6-phosphate dehydrogenase and transketolase, abolished the hydrogen peroxide-dependent alterations in fructose 1,6-bisphosphate steady-state levels and pyruvate accumulation, respectively. These findings suggest that a substantial fraction of glucose-derived carbon flux is diverted to the pentose phosphate pathway under oxidative stress, underscoring the importance of feedforward control in maintaining redox balance.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103740"},"PeriodicalIF":10.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515944","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}

{"title":"Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice","authors":"Márton Kokas ,&nbsp;András Budai ,&nbsp;Andrea Kádár ,&nbsp;Soroosh Mozaffaritabar ,&nbsp;Lei Zhou ,&nbsp;Tímea Téglás ,&nbsp;Rebeka Sára Orova ,&nbsp;Dániel Gáspár ,&nbsp;Kristóf Németh ,&nbsp;Daniel Marton Toth ,&nbsp;Nabil V. Sayour ,&nbsp;Csenger Kovácsházi ,&nbsp;Andrea Xue ,&nbsp;Réka Zsuzsanna Szatmári ,&nbsp;Beáta Törőcsik ,&nbsp;Domokos Máthé ,&nbsp;Noémi Kovács ,&nbsp;Krisztián Szigeti ,&nbsp;Péter Nagy ,&nbsp;Ildikó Szatmári ,&nbsp;Attila Ambrus","doi":"10.1016/j.redox.2025.103743","DOIUrl":"10.1016/j.redox.2025.103743","url":null,"abstract":"<div><div>The alpha-ketoglutarate dehydrogenase complex (KGDHc), also known as the 2-oxoglutarate dehydrogenase complex, plays a crucial role in oxidative metabolism. It catalyzes a key step in the tricarboxylic acid (TCA) cycle, producing NADH (primarily for oxidative phosphorylation) and succinyl-CoA (for substrate-level phosphorylation, among others). Additionally, KGDHc is also capable of generating reactive oxygen species, which contribute to mitochondrial oxidative stress. Hence, the KGDHc and its dysfunction are implicated in various pathological conditions, including selected neurodegenerative diseases. The pathological roles of KGDHc in these diseases are generally still obscure.</div><div>The aim of this study was to assess whether the mitochondrial malfunctions observed in the dihydrolipoamide succinyltransferase (<em>DLST</em>) and dihydrolipoamide dehydrogenase (<em>DLD</em>) double-heterozygous knockout (DLST^+/−DLD^+/−, DKO) mice are associated with neuronal and/or metabolic abnormalities.</div><div>In the DKO animals, the mitochondrial O₂ consumption and ATP production rates both decreased in a substrate-specific manner. Reduced H₂O₂ production was also observed, either due to Complex I inhibition with α-ketoglutarate or reverse electron transfer with succinate, which is significant in ischaemia-reperfusion injury. Middle-aged DKO mice exhibited minor cognitive decline, associated with microgliosis in the cerebral cortex and neuronal death in the <em>Cornu Ammonis</em> subfield 1 (CA1) of the hippocampus, indicating neuroinflammation. This was supported by increased levels of dynamin-related protein 1 (Drp1) and reduced levels of mitofusin 2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in DKO mice. Observations on activity, food and oxygen consumption, and blood amino acid and acylcarnitine profiles revealed no significant differences. However, middle-aged DKO animals showed decreased performance in the treadmill fatigue-endurance test as compared to wild-type animals, accompanied by subtle resting cardiac impairment, but not skeletal muscle fibrosis.</div><div>In conclusion, DKO animals compensate well the double-heterozygous knockout condition at the whole-body level with no major phenotypic changes under resting physiological conditions. However, under high energy demand, middle-aged DKO mice exhibited reduced performance, suggesting a decline in metabolic compensation. Additionally, microgliosis, neuronal death, decreased mitochondrial biogenesis, and altered mitochondrial dynamics were observed in DKO animals, resulting in minor cognitive decline. This is the first study to highlight the <em>in vivo</em> changes of this combined genetic modification. It demonstrates that unlike single knockout rodents, double knockout mice exhibit phenotypical alterations that worsen under stress situations.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103743"},"PeriodicalIF":10.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515920","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}

{"title":"Evidence for alcohol-mediated hemolysis and erythrophagocytosis","authors":"Chaowen Zheng ,&nbsp;Siyuan Li ,&nbsp;Johannes Mueller ,&nbsp;Cheng Chen ,&nbsp;Huanran Lyu ,&nbsp;Guandou Yuan ,&nbsp;Ane Zamalloa ,&nbsp;Lissette Adofina ,&nbsp;Parthi Srinivasan ,&nbsp;Krishna Menon ,&nbsp;Nigel Heaton ,&nbsp;Stephan Immenschuh ,&nbsp;Ines Silva ,&nbsp;Vanessa Rausch ,&nbsp;Seddik Hammad ,&nbsp;Steven Dooley ,&nbsp;Shilpa Chokshi ,&nbsp;Antonio Riva ,&nbsp;Songqing He ,&nbsp;Sebastian Mueller","doi":"10.1016/j.redox.2025.103742","DOIUrl":"10.1016/j.redox.2025.103742","url":null,"abstract":"<div><div>Alcohol-related liver disease (ALD) is the most common liver disease worldwide; however, its underlying molecular mechanisms remain poorly understood. Here, we identify ethanol-mediated hemolysis and erythrophagocytosis as major contributors to ALD pathogenesis using both in vitro and in vivo models, as well as surrogate markers such as heme oxygenase-1 (HO-1) and CD163, a scavenger receptor for hemoglobin-haptoglobin complexes.</div><div>A key initial observation was the direct optical evidence of serum hemolysis in heavy drinkers, which diminished after one week of alcohol withdrawal. In parallel, soluble CD163 (sCD163) levels declined during alcohol detoxification correlating with liver damage and fibrosis stages. Moreover, red blood cells (RBCs) from heavy drinkers exhibited increased fragility under hemolytic stress. In ethanol-fed mice, we also observed serum hemolysis. Erythrophagocytosis in liver tissue was visualized by co-localization of CD163 and hemoglobin autofluorescence. In vitro studies confirmed that ethanol – at concentrations transiently present in the upper gastrointestinal tract during alcohol ingestion – directly induces hemolysis and primes RBCs for erythrophagocytosis through eryptosis, marked by externalization of phosphatidylserine. Both heme, released during hemolysis, and bilirubin, its degradation product, further amplified erythrophagocytosis at clinically relevant concentrations, suggesting a self-perpetuating cycle. The antioxidant N-acetylcysteine efficiently blocked ethanol-induced RBC priming for erythrophagocytosis.</div><div>In conclusion, alcohol triggers a cascade of hemolysis, eryptosis, and erythrophagocytosis that may contribute to the pathogenesis of alcoholic hepatitis and end-stage ALD. sCD163 could serve as a noninvasive marker of hemolysis-associated macrophage activation. This mechanism opens new avenues for antioxidant-based therapies and may help to explain typical iron abnormalities, including ferroptosis, and hyperbilirubinemia in ALD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103742"},"PeriodicalIF":10.7,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511025","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}