Redox Biology最新文献

{"title":"Histone lactylation-induced premature senescence contributes to 1-nitropyrene-Induced chronic obstructive pulmonary disease","authors":"Rong-Rong Wang ,&nbsp;Dan-Lei Chen ,&nbsp;Meng Wei ,&nbsp;Se-Ruo Li ,&nbsp;Peng Zhou ,&nbsp;Jing Sun ,&nbsp;Qi-Yuan He ,&nbsp;Jin Yang ,&nbsp;Hui Zhao ,&nbsp;Lin Fu","doi":"10.1016/j.redox.2025.103703","DOIUrl":"10.1016/j.redox.2025.103703","url":null,"abstract":"<div><div>Our previous study revealed that mice exposed to 1-nitropyrene (1-NP) develop pulmonary fibrosis and senescent alveolar cells. However, the impacts of chronic 1-NP on chronic obstructive pulmonary disease (COPD) and the underlying mechanism are unclear. Our research suggested that chronic 1-NP evoked alveolar structure damage, inflammatory cell infiltration, and pulmonary function decline in mice. Moreover, 1-NP increased p53 and p21 expression, the number of β-galactosidase-positive cells, and cell cycle arrest in mouse lungs and MLE-12 cells. Moreover, 1-NP promoted glycolysis and upregulated lactic dehydrogenase A (LDHA) and lactate production in mouse lungs and MLE-12 cells. Elevated glycolysis provoked histone lactylation, but not histone acetylation in pulmonary epithelial cells. Mechanistically, histone H3 lysine 14 lactylation (H3K14la) was upregulated in pulmonary epithelial cells. <em>P53</em> knockdown mitigated 1-NP-induced cell cycle arrest and senescence in MLE-12 cells. CUT&amp;Tag and ChIP-qPCR experiments confirmed that increased H3K14la directly upregulated <em>p53</em> transcription in pulmonary epithelial cells. As expected, <em>LDHA</em> knockdown alleviated 1-NP-triggered cell cycle arrest and senescence in MLE-12 cells. In addition, supplementation with oxamate, an inhibitor of LDH, attenuated 1-NP-incurred premature senescence and the COPD-like phenotype in mice. These data revealed for the first time that histone lactylation-induced the increase in p53 transcription contributes to pulmonary epithelial cell senescence during 1-NP-induced COPD progression. Our results provide a basis for repressing lactate production as a promising therapeutic strategy for COPD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103703"},"PeriodicalIF":10.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177639","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":"Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11","authors":"Zheng Xiao ,&nbsp;Yucheng Pan ,&nbsp;Hong Meng ,&nbsp;Zongze Qu ,&nbsp;Liang Guo ,&nbsp;Bin Kong ,&nbsp;Wei Shuai ,&nbsp;He Huang","doi":"10.1016/j.redox.2025.103704","DOIUrl":"10.1016/j.redox.2025.103704","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic cardiomyopathy (DCM) is a prevalent and severe complication of diabetes, for which effective management strategies remain limited. Ubiquitin-specific protease 38 (USP38) has been associated with various cardiovascular diseases. In this study, we investigate the role of USP38 in the pathogenesis of DCM.</div></div><div><h3>Methods</h3><div>Cardiomyocyte-specific transgenic and knockout USP38 mice were generated, and diabetic mouse model was established using streptozotocin injections. Neonatal rat cardiomyocytes exposed to high glucose conditions were utilized for in vitro experiments. Cardiac remodeling was assessed through echocardiography, electrophysiological analysis, histological assessment, and molecular analysis.</div></div><div><h3>Results</h3><div>USP38 expression was significantly upregulated in DCM. Cardiomyocyte-specific USP38 overexpression aggravated cardiac dysfunction, cardiac inflammation and myocardial fibrosis, mitochondrial dysfunction, and increased vulnerability to ventricular arrhythmia in diabetic mice. Conversely, cardiomyocyte-specific USP38 deletion improved cardiac structural and electrical remodeling and attenuated mitochondrial impairment. Similar results were observed in vitro. Mechanistically, RNA-sequencing analysis, immunoprecipitation and mass spectrometry analysis and lipidomic analysis demonstrated that USP38 directly interacts with Acy-CoA dehydrogenase (ACAD11), deubiquitinating and inactivating it. This leads to abnormal fatty acid oxidation and subsequent activation of the receptor for advanced glycation end products (RAGE) pathway in diabetic heart. Pharmacological inhibition of RAGE using FPS-ZM1 hampered cardiac remodeling and dysfunction in cardiomyocyte-specific USP38 overexpressing diabetic mice.</div></div><div><h3>Conclusion</h3><div>The study demonstrates that USP38 exacerbates diabetes-induced cardiac remodeling and DCM via post-translational modification of ACAD11, highlighting a novel therapeutic target for DCM.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103704"},"PeriodicalIF":10.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196201","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":"Redox signaling-mediated S-glutathionylation of protein disulfide isomerase A1 initiates intrinsic apoptosis and contributes to accelerated aging","authors":"Zhi-Wei Ye ,&nbsp;Jie Zhang ,&nbsp;Amit Kumar ,&nbsp;Xuejian Huang ,&nbsp;Theodore L. Mathuram ,&nbsp;Andrew D. Mccall ,&nbsp;John Culpepper ,&nbsp;Leilei Zhang ,&nbsp;Anthony D. Curione ,&nbsp;Jianqiang Xu ,&nbsp;Kenneth D. Tew ,&nbsp;Danyelle M. Townsend ,&nbsp;Anna Blumental-Perry","doi":"10.1016/j.redox.2025.103680","DOIUrl":"10.1016/j.redox.2025.103680","url":null,"abstract":"<div><div>Identifying factors that contribute to the age-related onset of chronic obstructive pulmonary disease (COPD) is crucial for its prevention and treatment. The multifunctional endoplasmic reticulum (ER) chaperone protein disulfide isomerase A1 (PDIA1) shows a protective increase in expression levels in human and mouse non-COPD smokers. However, this increase slows with aging and disease progression, while increase in glutathione S-transferase <strong>π</strong>1 (GSTP1) does not. PDI has redox sensitive cysteine residues that can become S-glutathionylated (PDI-SSG) which compromise both isomerase and chaperone activity. Oxidized PDIA1 levels progressively rise with age in the lungs of murine non-smokers, with an even greater increase in smokers. To investigate whether an increased oxidized-to-native PDIA1 ratio (PDI-SSG/PDI-SH) contributes to the depletion of alveolar epithelial type 2 progenitor cells in COPD, we used the type-2-like cell line MLE12. High doses of cigarette smoke (CS) induced elevated oxidized PDIA1 levels, while a redox-refractory PDIA1 variant maintained a lower PDI-SSG/PDI-SH. Upon CS exposure, PDIA1 was S-glutathionylated by GSTP1 and predominantly localized at the ER–mitochondria interface. This mitochondrial proximity was prevented by pharmacological or genetic GSTP1 inhibition. When localized at the ER–mitochondria interface, S-glutathionylated PDIA1 decreased mitochondrial membrane potential (MMP), facilitated mitochondrial permeability transition pore opening, decreased mitochondrial respiration and triggered cytochrome <em>c</em> (<em>Cyt c</em>) release, followed by caspase-3 activation. Isolated mitochondrial studies confirmed that PDI-SSG trigger these apoptotic signals whereas native PDI does not. Our findings indicate that GSTP1-mediated S-glutathionylation of PDIA1 drives pro-apoptotic intraorganellar signaling by altering its ER distribution. Overexpression of a redox-refractory PDIA1 variant restored MMP and reduced <em>Cyt c</em> release, suggesting that a lower S-glutathionylated-to-native PDIA1 ratio is protective. These findings highlight a threshold-dependent regulation of PDIA1-SSG/PDIA1-SH redox signaling. We propose that the simultaneous inability to maintain high PDIA1 levels and the age-associated increase in its S-glutathionylated form in smokers accelerates AEC2 depletion and exhaustion, thereby contributing to emphysema progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103680"},"PeriodicalIF":10.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204775","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":"Autophagy hub-protein p62 orchestrates oxidative, endoplasmic reticulum stress, and inflammatory responses post-ischemia, exacerbating stroke outcome","authors":"Xingyun Quan ,&nbsp;Yukun Yang ,&nbsp;Xiaolong Liu ,&nbsp;Britta Kaltwasser ,&nbsp;Matthias Pillath-Eilers ,&nbsp;Bernd Walkenfort ,&nbsp;Sylvia Voortmann ,&nbsp;Ayan Mohamud Yusuf ,&nbsp;Nina Hagemann ,&nbsp;Chen Wang ,&nbsp;Mike Hasenberg ,&nbsp;Dirk M. Hermann ,&nbsp;Ulf Brockmeier","doi":"10.1016/j.redox.2025.103700","DOIUrl":"10.1016/j.redox.2025.103700","url":null,"abstract":"<div><div>Autophagy has crucial roles for ischemia/reperfusion (I/R) injury. To define the role of the autophagy hub protein p62/SQSTM1 in I/R injury, we conducted gain-of-function and loss-of-function experiments in a set of cell types, including two neuron-like cell lines, primary neurons, brain endothelial and astroglial-like cells, which we combined with mouse ischemic stroke studies. p62 levels post-I/R increased alongside intracellular ROS changes. p62 overexpression increased and p62 knockdown or pharmacological deactivation reduced I/R injury. Autophagic flux was p62-dependent, but oxygen-independent. Using p62 domain deletion mutants we identified p62's ZZ domain as key factor mediating autophagy and cell death. Death-promoting effects of p62 involved elevated ROS burden. At the same time, p62 activated a broad network of cytoprotective responses, which included NRF2-associated antioxidant signaling and inhibition of the pro-inflammatory NFκB pathway, which were bidirectionally linked with p62, and downregulation of the ER stress sensor BiP/GRP78 with consecutive activation of the UPR PERK branch. Our study establishes p62 as a master regulator of I/R injury, which offers itself as target for stroke therapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103700"},"PeriodicalIF":10.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196117","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":"Redox-signaling in innate immune memory: Similar mechanisms in animals/humans and plants","authors":"Christian Lindermayr ,&nbsp;Ali Önder Yildirim","doi":"10.1016/j.redox.2025.103702","DOIUrl":"10.1016/j.redox.2025.103702","url":null,"abstract":"<div><div>Plants and animals/humans have evolved sophisticated innate immune systems to cope with microbial attack. Innate immunity implies the presence of membrane-located and intracellular receptors to recognize compounds released by damage or by invading pathogens. After detection the receptor molecules initiate intracellular defense signaling, resulting in cell death and/or production of defense molecules. Interestingly, the defense response includes also memory mechanisms, which allow the organisms to better cope with future microbial attacks. Redox mechanisms play an important role in defense signaling. In this review article, we compare the innate immune memory of animals/humans and plants and describe how reversible nitric oxide- and reactive oxygen species-dependent protein modifications enable the activation of defense signaling proteins and transcription factors and regulate the activity of chromatin modifying enzymes to establish innate immune memory. We hope to encourage efforts to characterize further molecular redox mechanisms of the innate immune memory, which might enable the development of new immunotherapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103702"},"PeriodicalIF":10.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169913","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":"Divergent redox responses of macular and peripheral Müller Glia: Implications for retinal vulnerability","authors":"Ting Zhang ,&nbsp;Kaiyu Jin ,&nbsp;Shaoxue Zeng ,&nbsp;Penghui Yang ,&nbsp;Meidong Zhu ,&nbsp;Jialing Zhang ,&nbsp;Yingying Chen ,&nbsp;Sora Lee ,&nbsp;Michelle Yam ,&nbsp;Yue Zeng ,&nbsp;Xiaoyan Lu ,&nbsp;Lipin Loo ,&nbsp;G. Gregory Neely ,&nbsp;Andrew Chang ,&nbsp;Fanfan Zhou ,&nbsp;Jianhai Du ,&nbsp;Xiaohui Fan ,&nbsp;Ling Zhu ,&nbsp;Mark C. Gillies","doi":"10.1016/j.redox.2025.103691","DOIUrl":"10.1016/j.redox.2025.103691","url":null,"abstract":"<div><div>The macula is preferentially affected in some common retinal diseases (such as age-related macular degeneration, diabetic retinopathy and macular telangiectasia type 2), whereas most inherited retinal degenerations (e.g., retinitis pigmentosa) tend to initially affect the peripheral retina. This pattern suggests the macula may have intrinsic vulnerabilities in its oxidative stress defences, compared to the periphery. Profiling of single-cell level transcriptional changes found that the peripheral retina exhibited greater transcriptional alterations than the macula in response to stress. One pronounced change was in a subgroup of Müller glia (MG) that was dominant in the peripheral retina. Genes more abundantly expressed in peripheral MG were mainly associated with redox regulation, oxidative stress responses and cellular detoxification and were more influenced by oxidative insults, such as light-induced stress. In contrast, genes highly expressed in macular MG were primarily involved in cellular homeostasis and neuroprotection, showing less responsiveness to oxidative challenges. Notably, Metallothionein 1 (MT1), A-Kinase Anchor Protein 12 (AKAP12) and MAF BZIP Transcription Factor F (MAFF) were significantly more expressed in peripheral MG than in macular MG, indicating a region-specific redox regulatory mechanism. Knockdown of these genes in primary MG led to decreased viability under oxidative stress, suggesting their role in antioxidant defence. Our findings indicate that macular MG prioritise retinal function over redox adaptation, which may contribute to their vulnerability to degenerative diseases associated with oxidative damage. These insights underscore the importance of region-specific redox homeostasis in retinal health and disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103691"},"PeriodicalIF":10.7,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144239637","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":"Colorectal cancer mortality is associated with low selenoprotein P status at diagnosis","authors":"Stefanie Brezina ,&nbsp;Thilo Samson Chillon ,&nbsp;Sabrina Asaad ,&nbsp;Andreas Maieron ,&nbsp;Julian Prosenz ,&nbsp;Julian Seelig ,&nbsp;Kamil Demircan ,&nbsp;David J. Hughes ,&nbsp;Andrea Gsur ,&nbsp;Lutz Schomburg","doi":"10.1016/j.redox.2025.103701","DOIUrl":"10.1016/j.redox.2025.103701","url":null,"abstract":"<div><div>Selenium (Se) deficiency, affecting hundreds of millions of individuals worldwide, is linked to increased incidence of colorectal cancer (CRC), yet tumors paradoxically accumulate Se to evade ferroptosis and promote metastasis. Therefore, understanding the prognostic impact of Se status at diagnosis is crucial to consider and enable personalized interventions.</div><div>Four Se markers, namely total-Se, the circulating selenoproteins GPx3 and SELENOP, and autoantibodies to SELENOP, were analyzed in participants of the ongoing Colorectal Cancer Study of Austria (CORSA). Final analyses included 519 participants (n = 153 tumor-free, n = 255 adenoma and n = 111 CRC). Subjects were enrolled following a positive fecal immunochemical test, underwent a colonoscopy for diagnosis, and were followed up for 15 years.</div><div>Total-Se concentration and GPx3 activity did not differ across groups, but SELENOP concentrations were lower in CRC (median (IQR); controls: 2.9 (0.9), adenoma: 2.8 (1.0), CRC: 2.4 (0.9); p &lt; 0.001). Prevalence of SELENOP autoimmunity was &lt;1 % in controls, but &gt;5 % in patients. Total Se and SELENOP levels above the median were associated with better survival in all groups. SELENOP displayed an inverse association with mortality in fully adjusted models (HR(CI) per SD for SELENOP; controls: 0.62(0.46–0.83), adenomas: 0.73(0.59–0.90), CRC: 0.64(0.49–0.84)). Adding any Se biomarker, particularly SELENOP, to a model with established clinical parameters improved prognostication, and the highest prognostic values were observed when including SELENOP or all three Se biomarkers. Data-driven clustering analysis identified three distinct clusters based on Se markers, one of which displayed a remarkably increased risk for mortality (HR; 1.8).</div><div>We conclude that SELENOP deficiency at the time of diagnosis is inversely associated with mortality risk and improves prognostication over clinical parameters. As selenoprotein expression is a modifiable parameter mainly dependent on selenium intake, the personalized correction of a diagnosed deficiency should be investigated in future studies to improve CRC patient survival.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103701"},"PeriodicalIF":10.7,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154615","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":"Histones in neutrophil extracellular traps (NETs) contain oxidative post-translational modifications induced by the myeloperoxidase oxidant hypochlorous acid","authors":"Helen Hemmling,&nbsp;Line A.E. Hallberg,&nbsp;Per Hägglund,&nbsp;Clare L. Hawkins","doi":"10.1016/j.redox.2025.103696","DOIUrl":"10.1016/j.redox.2025.103696","url":null,"abstract":"<div><div>Extracellular traps (NETs) released by neutrophils during inflammation play a role in clearing infection but also contribute to disease pathology. NETs consist of a DNA backbone containing histones, anti-microbial granule proteins, such as myeloperoxidase (MPO), and other proteins. MPO remains enzymatically active and generates hypochlorous acid (HOCl) to kill pathogens. However, HOCl also readily reacts with proteins, but whether histones and other NET proteins are modified by this oxidant is unknown. This is significant as post-translational modification of histones alters their intracellular and extracellular reactivity. In this study, we used a proteomic approach to characterise the protein composition of NETs and identify HOCl-induced oxidative modifications on histones and other proteins. NETs were collected from primary neutrophils and the PLB-985 cell line and stimulated with phorbol myristate acetate (PMA) or nigericin, a bacterial peptide derived from <em>Streptomyces hygroscopicus</em>. There was evidence for Lys nitrile and aminoadipic semialdehyde formation, Tyr and Trp chlorination, and Met oxidation on histones and other proteins, including quinone oxidoreductase. Chlorination of Tyr-88 on histone H4 was particularly abundant and occurred to a greater extent in NETs from neutrophils exposed to PMA compared to nigericin, consistent with nigericin triggering NET release via a non-oxidative pathway. Chlorination of histone H4 Tyr-88 was also observed in the nuclear and cytoplasmic cell extracts of stimulated cells and could be decreased on treatment of the neutrophils with the MPO inhibitor AZD5904. These findings provide the first evidence that HOCl modifies proteins within NETs, particularly histone H4, which may be relevant in disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103696"},"PeriodicalIF":10.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185313","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":"Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer","authors":"Jingwen Chen ,&nbsp;Yedi Huang ,&nbsp;Daocheng Zuo ,&nbsp;Ruimin Shan ,&nbsp;Songmao Li ,&nbsp;Ran Li ,&nbsp;Dong Hua ,&nbsp;Qiang Zhan ,&nbsp;Xudong Song ,&nbsp;Yun Chen ,&nbsp;Pei Ma ,&nbsp;Ling Ma ,&nbsp;Guoquan Tao ,&nbsp;Yongqian Shu","doi":"10.1016/j.redox.2025.103693","DOIUrl":"10.1016/j.redox.2025.103693","url":null,"abstract":"<div><h3>Aims</h3><div>This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on the interplay between ferroptosis and lipid metabolism of tumor cells.</div></div><div><h3>Methods</h3><div>We constructed FGFR-TKI-resistant cell lines from GC cells. RNA sequencing was performed to identify differentially expressed genes (DEGs) related to ferroptosis and assess lipid metabolism in resistant cells. GC microenvironment lipid profile was characterized by HPLC-MS/MS lipidomics. The effects of CHAC1 and cholesterol synthesis modulation on ferroptosis and FGFR-TKI resistance were assessed using in vitro and in vivo models.</div></div><div><h3>Results</h3><div>We found that FGFR-TKI can induce ferroptosis in FGFR-TKI-sensitive cells, while resistant cells exhibit decreased sensitivity to ferroptosis due to reduced CHAC1 expression, a key glutathione-specific degrading enzyme. Overexpression of CHAC1 enhances FGFR-TKI cytotoxicity. Additionally, cholesterol accumulation in resistant cells, associated with diminished stearic acid (SA) uptake, confers FGFR-TKI-induced ferroptosis resistance. In vivo studies show that CHAC1 overexpression or cholesterol synthesis inhibition can reverse FGFR-TKI resistance, which is dependent on ferroptosis.</div></div><div><h3>Conclusions</h3><div>Dysregulated lipid homeostasis downregulated CHAC1-mediated ferroptosis, leading to FGFR-TKI resistance in gastric cancer. Overexpression of CHAC1 or inhibiting cholesterol synthesis presents promising therapeutic strategies to overcome FGFR-TKI resistance in GC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103693"},"PeriodicalIF":10.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189392","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":"IDO1 improves postischemic neovascularization in aged mice by boosting endothelial NAD+ de novo synthesis and curbing endothelial senescence","authors":"Minghong Chen ,&nbsp;Junyu Chen ,&nbsp;Yu Liu ,&nbsp;Jing Chen ,&nbsp;Meilian Yao ,&nbsp;Xuerui Wang ,&nbsp;Jian Zhang ,&nbsp;Miao Pan ,&nbsp;Jipeng Zhou ,&nbsp;Yongping Bai","doi":"10.1016/j.redox.2025.103695","DOIUrl":"10.1016/j.redox.2025.103695","url":null,"abstract":"<div><h3>Introduction</h3><div>Peripheral arterial disease (PAD) is prevalent among the elderly, and therapeutic neovascularization is a research hotspot in PAD treatment. Supplementing nicotinamide adenine dinucleotide (NAD⁺) precursors is an important approach for promoting neovascularization, but clinical trials in the elderly PAD patients have shown limited success. This study aims to find effective ways to boost NAD⁺ levels in elderly PAD patients to enhance neovascularization.</div></div><div><h3>Methods</h3><div>Transcriptome and NAD⁺-targeted metabolomics analyses were conducted on ischemic hindlimb muscle endothelial cells (ECs). The role of indoleamine 2,3-dioxygenase 1 (IDO1) in postischemic neovascularization was studied using global knockout mice. Mechanisms regulating IDO1 expression were investigated through transcriptomics and functional experiments. The effects of IDO1 protein on postischemic neovascularization were evaluated <em>in vivo</em> and <em>in vitro</em>. Plasma IDO1 levels were measured in young and elderly PAD patients and correlated with clinical indicators of PAD.</div></div><div><h3>Results</h3><div>In aged mice, ECs exhibited decreased NAD⁺ de novo synthesis and IDO1 transcription. IDO1 deficiency induced the decline of ECs NAD⁺ de novo synthesis and ECs senescence, impaired neovascularization in young mice. Elevated IL-17A/F inhibited IDO1 transactivation via CREB, impairing neovascularization. IDO1 administration alleviated the decline of ECs NAD⁺ de novo synthesis and ECs senescence, and enhanced neovascularization in aged mice. Plasma IDO1 levels were lower in elderly PAD patients, correlating positively with disease severity, onset risk, and cardiovascular outcomes.</div></div><div><h3>Conclusion</h3><div>ECs NAD⁺ metabolism imbalance is driven by decreased de novo synthesis of NAD⁺ and targeting IDO1 to elevate NAD⁺ levels could be a potential therapeutic direction for elderly PAD patients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103695"},"PeriodicalIF":10.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154616","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}