Redox Biology最新文献

{"title":"Corrigendum to \"Dimethyl malonate preserves brain and neurobehavioral phenotype following neonatal hypoxia-ischemia by inhibiting FTH1-mediated ferritinophagy\" [Redox Biol. 86 (2025) 103792].","authors":"Yiming Jin,Xinxin Wang,Xiaowen Xu,Xiuwen Zhou,Qing Wang,Li Zhang,Lili Li,Meifang Jin,Hong Ni","doi":"10.1016/j.redox.2025.103882","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103882","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"39 1","pages":"103882"},"PeriodicalIF":11.4,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277388","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":"Beyond energy: Mitochondrial control of platelet lifecycle through redox, calcium, and dynamics.","authors":"Xinle Wang,Rui Liao,Qihang Huang,Jingyan Li,Xiang Li,Xiaolin Gan,Yiwei Wang,Chunling Zhao,Qibing Mei,Jianping Chen,Anguo Wu,Xiaogang Zhou,Jianming Wu","doi":"10.1016/j.redox.2025.103892","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103892","url":null,"abstract":"Platelet disorders, caused by quantitative deficiencies or functional impairments, significantly contribute to cardiovascular, neurological, and iatrogenic pathologies. Although platelets are indispensable for hemostasis, thrombosis, and immune responses, the molecular mechanisms governing their biogenesis from megakaryocytes (MKs) and subsequent functional regulation remain incompletely understood. Mitochondria, inherited from MK progenitors, are now recognized as central regulators of platelet physiology and pathology. Emerging evidence demonstrates that mitochondrial processes critically regulate MK differentiation and thrombopoiesis, unveiling novel pathways in platelet formation. Mitochondria regulate metabolism, calcium (Ca2+) regulation, reactive oxygen species (ROS) signaling, autophagy, and dynamics, directly modulate essential platelet activities, such as activation dynamics, lifespan, and coagulation efficiency, in physiological and pathological contexts. This review synthesizes emerging evidence on the multi-layered mitochondrial control of thrombopoiesis and platelet functionality. We critically assess the translational potential of targeting mitochondria for treating platelet-related disorders, delineating specific molecular targets within MKs and platelets. Furthermore, we propose a framework for developing mitochondrial-based therapeutic strategies to prevent and manage platelet-associated diseases, thereby advancing clinical translation in this field.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"12 1","pages":"103892"},"PeriodicalIF":11.4,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305468","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":"Gestational low-protein diet impairs mitochondrial function and skeletal muscle development by inducing immune responses in male offspring.","authors":"Atilla Emre Altinpinar,Moussira Alameddine,Ufuk Ersoy,Ioannis Kanakis,Vanja Pekovic-Vaughan,Susan E Ozanne,Katarzyna Goljanek-Whysall,Aphrodite Vasilaki","doi":"10.1016/j.redox.2025.103890","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103890","url":null,"abstract":"Maternal nutrition is essential for proper fetal and postnatal organ maturation and is linked to the future risk of developing metabolic syndrome, cardiovascular disease, and muscle loss. There is still limited understanding how a low-protein intake during gestation influences skeletal muscle development, inflammation, and the related pathways. This study aimed to investigate the impact of gestational low-protein diet in mice on skeletal muscle development and inflammatory responses in male offspring. Pups born from mothers fed a low-protein diet (LPD) were lactated by normal protein diet (NPD)-fed mothers and maintained on NPD post-weaning (LNN group). Offspring born from mothers fed an NPD and maintained on an NPD during lactation and beyond were used as controls (NNN group). In 21-day-old offspring from protein-restricted mothers, RNA-Seq analysis showed upregulation of immune response-related genes, enriching adaptive immunity pathways. Additionally, LNN group exhibited elevated markers of inflammation, along with disruptions in antioxidant defence balance and macrophages infiltration in gastrocnemius muscle at 3 months of age. Energy metabolism was impaired, as indicated by changes in related proteins and enzymes involved in mitochondrial function. We conclude that gestational LPD adversely affects skeletal muscle development in male offspring.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"104 1","pages":"103890"},"PeriodicalIF":11.4,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305471","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":"FOXF1 and SHH participate in the regulation of iron signaling in pulmonary fibrosis.","authors":"Xue Wang,Xin Liu,Yumei Fan,Ke Tan,Jiaqi Gao,Yuejiao Wang,Ziyi Zhang,Shuyue Liu,Xiaofan Wang,Baohua Wang,Pengxiu Cao","doi":"10.1016/j.redox.2025.103893","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103893","url":null,"abstract":"Pulmonary fibrosis (PF) involves persistent activation of fibroblasts and excessive deposition of extracellular matrix, with limited therapeutic options. Pulmonary iron overload has been identified in PF and is associated with the progression of PF. However, the underlying signaling pathway remains unclear. This study demonstrated that iron accumulates in the mouse lung from day 7 post-bleomycin (BLM) instillation until harvest, coinciding with the activation of pulmonary fibroblasts and the onset of fibrogenesis. Iron supplementation promoted the G1/S cell cycle transition and proliferation of fibroblasts, and worsened PF, whereas iron deficiency demonstrated the opposite effects. Mechanistically, both iron and reactive oxygen species (ROS) suppress Forkhead box F1 (FOXF1) expression. FOXF1 overexpression upregulates the expression of antioxidant proteins, including ferredoxin 1 (FDX1) and heme oxygenase-1 (HO-1). Both FOXF1 overexpression and FDX1 overexpression reduced cellular labile iron pool (LIP), ROS levels, and collagen synthesis in human pulmonary fibroblasts. Sonic hedgehog (SHH) signaling elevated intracellular iron, fibroblast proliferation, and its own secretion, establishing a sustained SHH/iron amplifying loop. These findings identify an iron/ROS-FOXF1 positive feedback loop and an SHH-iron self-promoting pathway that drive sustained elevated iron levels and persistent fibroblast activation and fibrogenesis, thereby deepening our understanding of the iron signaling in PF.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"46 1","pages":"103893"},"PeriodicalIF":11.4,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305469","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":"Emergence of NOX1/DUOX NADPH oxidases is a key feature of functional neutrophil reprogramming at the gut and lung barrier.","authors":"Ashish K Singh,Maurice O'Mara,Julie Drieu La Rochelle,Noemie Therry,Aurora D'Alessio,John Baugh,Ramya S Barre,Misaki Matsumoto,Aitor Nogales,Luis Martínez-Sobrido,Ulla G Knaus","doi":"10.1016/j.redox.2025.103883","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103883","url":null,"abstract":"Functional neutrophil diversity is recognized as a driver of development, progression and resolution of disease. Recruited neutrophils are imprinted by biochemical, biophysical and mechanical stimuli of the encountered microenvironment, altering their genetic and phenotypic program. The functional implications of this reprogramming are of critical importance for devising strategies to modify neutrophil behavior. Oxidant production affects neutrophil responses, shapes the microenvironment and often determines disease outcome in inflammation, infection and cancer. Here we report neutrophil diversification at mucosal barriers in inflammatory and infectious disease, culminating in tissue and stimulus-dependent de novo expression of the NADPH oxidases NOX1, DUOX2, and DUOX1 in recruited neutrophils. In contrast to proinflammatory DUOX2, myeloid NOX1 ameliorated colonic inflammation, yet epithelial NOX1 increased neutrophil recruitment from the onset, with a similar response observed in pulmonary S. aureus infection. In contrast, neutrophil DUOX expression did not alter S. aureus disease progression but extended host survival in influenza A virus infection. Thus, at gut and lung barriers an expansion of neutrophil oxidases occurs that highlights proinflammatory and antimicrobial DUOX2 activity, while NOX1 function seems intricate with multiple inputs. Evaluation of these de novo expressed oxidases in other neutrophil-driven diseases will further uncover their contribution to host protection and pathogenesis.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"59 1","pages":"103883"},"PeriodicalIF":11.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296045","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":"Bidirectional regulation of KEAP1 BTB domain-based sensor activity.","authors":"Takafumi Suzuki,Kenji Takagi,Tatsuro Iso,Huaichun Wen,Anqi Zhang,Tetsuya Hatakeyama,Hiraku Oshima,Tsunehiro Mizushima,Masayuki Yamamoto","doi":"10.1016/j.redox.2025.103885","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103885","url":null,"abstract":"The KEAP1-CUL3 ubiquitin ligase regulates protein stability of transcriptional factor NRF2 and plays critical roles in cellular stress response. The BTB domain of KEAP1 functions as a sensor for electrophilic chemicals. However, the precise mechanisms by which electrophiles are recognized and inhibit BTB activity remain unclear. Here, we show that electrophilic modification alters the spatial arrangement of the BTB homodimer, regulating its ligase activity. Co-crystal structural analyses and functional studies using potent NRF2-inducing CDDO-derivatives, synthetic electrophilic compounds structurally related to clinically approved molecules such as Omaveloxolone, revealed that the key sensor residue, Cys151, resides in a structurally elaborate environment within the BTB domain. Modification of Cys151 by NRF2 inducers changes the spatial configuration of the CUL3-binding sites in the BTB homodimer, reducing KEAP1-CUL3 complex affinity. In contrast, a Cys151-targeting NRF2 inhibitor induces an opposite rearrangement of the BTB homodimer. This study elucidates the molecular mechanism by which the BTB domain finely regulates KEAP1-CUL3 ubiquitin ligase activity.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"1 1","pages":"103885"},"PeriodicalIF":11.4,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296047","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":"Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway.","authors":"Yafei Jiao,Xinran Li,Jinming Guo,Chang Bei,Xintong Jiang,Houwu Jiang,Bingqian Mi,Tiantuan Jiang,Xiaohong Liu,Yaosheng Chen,Peiqing Cong,Zuyong He","doi":"10.1016/j.redox.2025.103886","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103886","url":null,"abstract":"Bone morphogenetic protein 15 (BMP15) is an oocyte-secreted growth factor, which interacts with ovarian follicular somatic cells and in turn promotes oocyte maturation. Disrupting BMP15 by CRISPR-ctRNP has been found to severely impair in vitro maturation (IVM) of porcine oocytes, accompanied with mitochondrial dysfunction and increased accumulation of reactive oxygen species (ROS). To investigate whether the plant-derived antioxidant quercetin (QUE) is able to rescue the IVM of BMP15-deficient oocytes, porcine oocytes microinjected with CRISPR-ctRNP targeting BMP15 were treated with 10 μM QUE, and we found that QUE can effectively rescue the impaired IVM of BMP15-deficient oocytes by restoring the impaired mitochondrial functions and reducing ROS through activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Activated ERK1/2 in turn inactivated glycogen synthase kinase-3β (GSK3β), which subsequently reduced Cyclophilin D (CypD) levels, and probably modulated the status of the permeability transition pore (PTP) of mitochondria, contributing to the reduced oxidative stress and apoptosis in porcine oocytes, and thus the improved oocyte quality and IVM. Our study further revealed the molecular mechanisms of QUE on alleviating oxidative stress of BMP15-deficient oocytes, suggesting that QUE may be a promising candidate for improving quality of oocytes with BMP15 mutations.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"117 1","pages":"103886"},"PeriodicalIF":11.4,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288259","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":"Oxidative modulation of Piezo1 channels.","authors":"N Novosolova, N Braidotti, T Patinen, T Laitinen, C Ciubotaru, K M Huttunen, A L Levonen, D Cojoc, R Giniatullin, T Malm","doi":"10.1016/j.redox.2025.103797","DOIUrl":"10.1016/j.redox.2025.103797","url":null,"abstract":"<p><p>Emerging evidence suggests that mechanosensitive Piezo1 channels play a role in the pathomechanism of various disorders. However, the mechanisms by which accumulating pathologies regulate Piezo1 activation remain unclear. Oxidative stress, a common feature of neurodegenerative diseases, is associated with generation of reactive oxygen species (ROS). While the dependence of Piezo1 channels on temperature, pH, and voltage has been well studied, the redox regulation of these highly mechanosensitive channels remains unknown. We investigated whether oxidative stress modulates the calcium permeability of Piezo1 channels using red blood cells (RBCs) and HEK293T cells transduced with Piezo1 as model systems. Additionally, using the selective H₂O₂ sensor HyPer7, we examined whether Piezo1 activation induces the generation of endogenous ROS. Using flow cytometry, Ca²⁺-imaging, patch clamp and microaspiration techniques we demonstrate that cell-permeable oxidants hydrogen peroxide (H₂O₂) and Chloramine-T, which specifically oxidize cysteines and methionines, inhibited Yoda1-induced activation of Piezo1 in both cell types. In contrast to Chloramine-T, the membrane-impermeable, cysteine-specific oxidant DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)) also inhibited Piezo1, although its inhibitory effect was less pronounced. Mechanical sensitivity of Piezo1 was reduced by H₂O₂ also in RBCs. Scavenging antioxidants N-acetylcysteine and dithiothreitol decreased or eliminated the inhibitory action of H₂O₂ and Chloramine-T. However, overexpression of the antioxidant transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2) did not prevent the inhibitory effects of Chloramine-T, suggesting a membrane-delimited site of redox modulation. Notably, Piezo1 activation slightly increased endogenous H2O2 production. Our data suggest that the reduced activity of Piezo1 in the oxidative environment is determined by oxidation of both cysteines and methionines, which are enriched in intracellular domains, with methionines playing a predominant role. Given the role of Piezo1 channels in pathophysiology of numerous disorders, we propose that, under conditions associated with oxidative stress, redox modulation of these mechanosensors could be a significant factor contributing to disease pathology.</p>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"103797"},"PeriodicalIF":11.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analysis of bipartite NRF2 activators that overcome feedback regulation for age-related chronic diseases.","authors":"Dmitry M Hushpulian, Navneet Ammal Kaidery, Priyanka Soni, Andrey A Poloznikov, Arpenik A Zakhariants, Alexandra V Razumovskaya, Mariia O Silkina, Vladimir I Tishkov, Eliot H Kazakov, Abraham M Brown, Irina N Gaisina, Young-Hoon Ahn, Sergey V Kazakov, Nancy Krucher, Sudarshana M Sharma, Bindu D Paul, Irina G Gazaryan, Sergey V Nikulin, Bobby Thomas","doi":"10.1016/j.redox.2025.103794","DOIUrl":"10.1016/j.redox.2025.103794","url":null,"abstract":"<p><p>Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The canonical Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other cellular proteins, causing side effects. However, when transitioning from homogeneous cell-free to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. We demonstrate that this discrepancy arises due to higher micromolar concentrations of Keap1 in cell lines. The absolute amounts of Nrf2 and Keap1 determined in brain sub-regions show more than an order of magnitude excess of Keap1 over Nrf2. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. Activation of the Nrf2-genetic program has a built-in feedback regulatory mechanism through Bach1, an Nrf2 transcriptional repressor, whose levels are elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, exhibits overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide, an Nrf2 activator, as well as with zinc and tin protoporphyrins, which are inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration.</p>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"103794"},"PeriodicalIF":11.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of molecular mechanisms of (Z)-3-(pentadec-10′-enyl)-catechol (litreol) and synthetic derivatives as inhibitors of human leukotriene biosynthesis","authors":"Alessia Maria Cossu ,&nbsp;Simona Pace ,&nbsp;Ferdinando Bruno ,&nbsp;Lucia Abbatiello ,&nbsp;Carmen Cerchia ,&nbsp;Emanuele Falbo ,&nbsp;Alejandra Catalina Muñoz Ramírez ,&nbsp;Christian Kretzer ,&nbsp;Laura Miek ,&nbsp;Fabiana Troisi ,&nbsp;Jana Gerstmeier ,&nbsp;Pasquale Ambrosino ,&nbsp;Silvia Zappavigna ,&nbsp;Antonio La vecchia ,&nbsp;Oliver Werz ,&nbsp;Michele Caraglia ,&nbsp;Rosanna Filosa","doi":"10.1016/j.redox.2025.103880","DOIUrl":"10.1016/j.redox.2025.103880","url":null,"abstract":"<div><div>5-Lipoxygenase (5-LO) catalyzes the early steps of leukotriene (LT) biosynthesis, making it an attractive target for anti-inflammatory drug development. This study provides a more detailed evaluation of the molecular mechanisms and pharmacological effects of litreol (CI), a natural compound from the Anacardiaceae family, along with its synthetic derivatives (CS, AS, and AI). The synthesis and biological evaluation of litreol analogs have already been previously published. Therefore, the aim of this article is to further explore their mechanisms of action, providing a more thorough investigation into their effects on 5-LO. Using both isolated human recombinant 5-LO in cell-free systems and cell-based assays, we evaluated the impact of the synthesized compounds on 5-LO product formation. Among them, CI and CS emerged as potent inhibitors, exhibiting IC₅₀ values of 0.26 μM and 0.80 μM in neutrophils, and 0.06 μM and 0.15 μM in cell-free assays, respectively. Notably, CI exhibited 2.5- to 3-fold greater potency compared to its hydrogenated analogue, CS. Both compounds also showed inhibitory activity against 12-lipoxygenase (12-LO) with IC₅₀ of 3.15 and 5.10 μM, respectively. Moreover, CI prevented the 5-LO/FLAP protein interaction and blocked both ERK-1/2 and p38 MAP kinase-dependent pathways required for 5-LO activation. Conversely, AS and AI derivatives did not show significant 5-LO inhibitory effects. Computational studies revealed that the differing binding modes and stability of CI and CS at the allosteric site of 5-LO explain their varying inhibitory effects. CI forms a stronger interaction network, supporting its higher potency, while CS shows greater flexibility and weaker interactions, correlating with lower activity. Additionally, the free catechol group is essential for activity, as its acetylation leads to loss of function. Overall, our findings highlight CI as a promising 5-LO inhibitor, in intact human leukocytes accounting for a novel potent anti-inflammatory compound.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103880"},"PeriodicalIF":11.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215939","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}