Antioxidants & redox signaling最新文献

{"title":"ALKBH5-Mediated m⁶A Demethylation Stabilizes HMGB1 to Drive Hepatocyte Pyroptosis and Liver Injury in Heat Stroke: Targeting via Biomimetic Nanodelivery.","authors":"Yanli Sun, Xiaolong Shu, Fei Guo","doi":"10.1177/15230864261449248","DOIUrl":"10.1177/15230864261449248","url":null,"abstract":"<p><strong>Aims: </strong>Heat stroke causes life-threatening liver injury, but its molecular basis remains poorly understood. We investigated whether ALKBH5-mediated N6-methyladenosine (m⁶A) demethylation stabilizes Hmgb1 transcripts and promotes hepatocyte pyroptosis through the NLRP3 inflammasome. We also developed mesenchymal stem cell membrane-coated glycyrrhizic acid liposomes (MMGLs) as a targeted therapeutic strategy.</p><p><strong>Results: </strong>RNA-seq of HS rat livers revealed significant enrichment of pyroptosis pathways, with ALKBH5 identified as a hub gene. Mechanistically, heat stress upregulated ALKBH5, which demethylated <i>HMGB1</i> mRNA, preventing its degradation and enhancing transcript stability. This stabilization led to increased intracellular High-mobility group box 1 (HMGB1) abundance, nucleocytoplasmic translocation, and extracellular release, subsequently activating the NLRP3-Caspase-1-GSDMD axis. Alkbh5 knockdown shortened Hmgb1 half-life and attenuated pyroptosis, whereas HMGB1 supplementation restored it. To target this axis, we engineered MMGLs (encapsulation efficiency: 81.7%), which exhibited superior inflammatory homing compared to unmodified liposomes. In HS rats, MMGLs achieved rapid hepatic accumulation, significantly reduced serum alanine aminotransferase/aspartate aminotransferase, and suppressed Interleukin-1 beta (IL-1β)/IL-18. MMGLs restored redox homeostasis by decreasing reactive oxygen species/malondialdehyde and boosting reduced glutathione/superoxide dismutase, thereby preserving hepatocyte architecture and inhibiting pyroptosis.</p><p><strong>Innovation: </strong>This study identifies an epitranscriptomic mechanism in HS-induced liver injury, in which ALKBH5-dependent stabilization of Hmgb1 mRNA amplifies pyroptotic signaling. MMGLs provide a biomimetic nanotherapeutic strategy to interrupt this inflammatory cascade.</p><p><strong>Conclusion: </strong>ALKBH5-mediated m⁶A demethylation stabilizes HMGB1 to drive hepatocyte pyroptosis during HS. MMGLs effectively target this axis, offering a promising therapeutic approach for acute liver damage. <i>Antioxid. Redox Signal.</i> 45, 173-197.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"173-197"},"PeriodicalIF":6.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of GPX8 Enhances Irradiation-Induced Ferroptosis Through m⁶A Hypomethylation-Mediated Upregulation of ACSL4 in Oral Cancer.","authors":"Xun Chen, Weidong Du, Jie Wu, Lejia Zhang, Yunyang Lu, Xiliu Zhang, Chao Wang, Shangwu Chen, Dongsheng Yu, Wei Zhao","doi":"10.1177/15230864261449406","DOIUrl":"10.1177/15230864261449406","url":null,"abstract":"<p><strong>Aims: </strong>Radioresistance limits the therapeutic efficacy of radiotherapy, and although ferroptosis contributes to radiation-induced tumor suppression, the upstream redox-epitranscriptomic mechanisms remain poorly defined. This study investigated how loss of the antioxidant enzyme glutathione peroxidase 8 (GPX8) influences susceptibility to ionizing radiation (IR), delineated the molecular pathway linking oxidative stress to ferroptosis, and evaluated the potential of GPX8 deletion as a radiosensitization strategy.</p><p><strong>Results: </strong>We identify GPX8 as a previously unrecognized suppressor of ferroptosis whose deletion markedly amplifies IR-induced ferroptotic cell death. GPX8 deficiency increased reactive oxygen species accumulation, lipid peroxidation, labile iron levels, and ferroptosis-associated gene expression following irradiation. Mechanistic dissection revealed a novel redox-epitranscriptomic axis: oxidative stress induced by GPX8 loss downregulated the transcription factor E2F4, which in turn reduced zinc-finger CCCH-type containing 13 (ZC3H13) expression, leading to N⁶-methyladenine (m⁶A) hypomethylation and stabilization of acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA. Overexpression of E2F4 or ZC3H13 reversed ACSL4 upregulation, confirming pathway causality. ACSL4 knockdown diminished ferroptosis and rescued the hypersensitivity of GPX8-deficient cells to IR. In an orthotopic xenograft model, GPX8-knockout tumors displayed significantly enhanced radiosensitivity and elevated ferroptotic markers, effects mitigated by the ferroptosis inhibitor liproxstatin-1.</p><p><strong>Innovation: </strong>This work uncovers a previously uncharacterized antioxidant-m⁶A-ferroptosis regulatory pathway and provides the first evidence that GPX8 modulates radiotherapy response by epitranscriptomic control of ACSL4 stability <i>via</i> the E2F4-ZC3H13 axis.</p><p><strong>Conclusion: </strong>GPX8 deletion sensitizes oral cancer to irradiation by promoting ferroptosis through oxidative stress-driven suppression of E2F4 and ZC3H13, resulting in m⁶A hypomethylation and stabilization of ACSL4 mRNA. GPX8 thus represents a promising target for ferroptosis-based radiosensitization. <i>Antioxid. Redox Signal.</i> 45, 219-241.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"219-241"},"PeriodicalIF":6.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet Mitochondria: A Promising Target for Antiplatelet Therapy.","authors":"Yan-Zhu Yao, Tong Yin, Yong-Ming Yao","doi":"10.1177/15230864261452350","DOIUrl":"10.1177/15230864261452350","url":null,"abstract":"<p><strong>Significance: </strong>Platelet mitochondria drive platelet activation and thrombosis by fueling energy demands <i>via</i> metabolic reprogramming, regulating calcium-mediated procoagulant signaling, and maintaining functional integrity through quality control mechanisms. Current antiplatelet agents, including P2Y12 antagonists, cyclooxygenase-1 inhibitors, glycoprotein IIb/IIIa blockers, and protease-activated receptor-1 antagonists, effectively prevent thrombosis but increase bleeding risk, underscoring the need for metabolism-targeting strategies.</p><p><strong>Recent advances: </strong>Here, we summarize key platelet mitochondrial mechanisms driving platelet activation: metabolic reprogramming through oxidative phosphorylation (OXPHOS)-to-glycolysis shifts, calcium flux mediated by the mitochondrial calcium uniporter controlling coagulation, quality control through dynamics and mitophagy, and mitochondrial genome (mtDNA) regulation linked to relevant diseases.</p><p><strong>Critical issues: </strong>The variable role of OXPHOS in thrombosis remains incompletely understood. Metabolic flexibility complicates therapeutic intervention, while the cytotoxic effects of mitochondrial modulators and technical limitations in the quantification of circulating mtDNA present significant translational challenges.</p><p><strong>Future directions: </strong>Development of therapies based on mitochondria-targeted antioxidants and metabolic enzyme modulators is proposed as a promising antiplatelet strategy. Transplantation of platelet-derived mitochondria and standardized detection of mtDNA warrant further exploration for thrombotic diseases. <i>Antioxid. Redox Signal.</i> 45, 265-292.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"265-292"},"PeriodicalIF":6.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the STAT5A-LCP2-NF-κB Pathway to Overcome PD-1 Resistance in Esophageal Cancer.","authors":"Yuan Zhang, Yunzhi Dang, Jun Wang, Bo Zhao, Zhibin Li, Xin Wang, Kun Liang","doi":"10.1177/15230864261452393","DOIUrl":"10.1177/15230864261452393","url":null,"abstract":"<p><strong>Aims: </strong>To investigate the tumor-intrinsic lymphocyte cytosolic protein 2 (LCP2) in esophageal squamous cell carcinoma (ESCA) and its molecular mechanisms in mediating resistance to programmed death-1 (PD-1) therapy.</p><p><strong>Methods: </strong>The expression of LCP2 in ESCA was analyzed using bioinformatics databases and further verified in clinical specimens. Functional studies employed patient-derived organoid models, xenograft models, and molecular assays to assess the impact of LCP2 knockout or overexpression on macrophage polarization, CD8 + T cell exhaustion, and PD-1 therapy response. Mechanistic investigations included nuclear factor-κB (NF-κB) inhibition, signal transducer and activator of transcription 5A (STAT5A) knockdown, chromatin immunoprecipitation, and dual-luciferase reporter assays.</p><p><strong>Results: </strong>LCP2 was markedly upregulated in ESCA and correlated with advanced stage, lymph node metastasis, and poor survival. Tumor-intrinsic LCP2 expression positively correlated with M2 macrophage polarization and sorted CD8⁺ T cell exhaustion. Mechanistically, this association depended on NF-κB pathway activation in EpCAM⁺ tumor fractions, while STAT5A transcriptionally regulates tumor-intrinsic LCP2 expression as an upstream transcription factor. Knockdown of tumor-intrinsic LCP2 or STAT5A in EpCAM⁺ tumor fractions suppressed the secretion of immunosuppressive cytokines and restored effector T cell function of sorted CD8⁺ T cells. <i>In vivo</i>, LCP2 depletion significantly inhibited tumor growth and synergized with PD-1 blockade. This synergistic effect was characterized by reduced tumor volume and increased CD8⁺ T cell infiltration. Overexpression of LCP2 reversed these effects, confirming its central role in immune escape.</p><p><strong>Conclusion: </strong>The STAT5A-LCP2-NF-κB axis remodels the immunosuppressive tumor microenvironment to mediate ESCA immune escape and PD-1 resistance. Targeting this regulatory axis provides a novel strategy to overcome immunotherapy resistance in esophageal cancer. <i>Antioxid. Redox Signal.</i> 45, 242-264.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"242-264"},"PeriodicalIF":6.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Endothelium-Derived Mitochondrial Reactive Oxygen Species on Obesity-Associated Atherosclerosis.","authors":"Tomoaki Yoshinaga, Takeshi Matsumura, Nobuhiro Kajihara, Yoshitaka Yagi, Minoru Takeshita, Yuqi Zhou, Kazuki Fukuda, Daisuke Kukidome, Takafumi Senokuchi, Miki Sato, Hiroyuki Motoshima, Tatsuya Kondo, Takeshi Nishikawa, Eiichi Araki, Naoto Kubota","doi":"10.1177/15230864261443843","DOIUrl":"10.1177/15230864261443843","url":null,"abstract":"<p><strong>Aims: </strong>Obesity, a risk factor for atherosclerosis development and progression, is marked by excessive reactive oxygen species (ROS) production. We previously demonstrated that high-glucose (HG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the link between elevated mtROS levels in obesity and atherosclerosis progression remains unclear. This study aimed to investigate whether endothelial-specific mtROS suppression by overexpressing manganese superoxide dismutase (MnSOD) could attenuate atherosclerosis progression in high-fat diet (HFD)-induced obese apolipoprotein E-deficient (ApoE KO) mice.</p><p><strong>Results: </strong>Atherosclerotic lesion formation did not differ significantly between normal chow-fed control ApoE KO mice and endothelial cell-specific MnSOD-overexpressing ApoE KO (eMnSOD-Tg/ApoE KO) mice. However, in HFD-fed groups, eMnSOD-Tg/ApoE KO mice exhibited reduced atherosclerotic lesion size, decreased relative ROS levels, and lower <i>Icam1</i> and <i>Ccl2</i> expression compared to HFD-fed control ApoE KO mice. In obese ApoE KO mice, serum glucose, lipopolysaccharide (LPS), and low-density lipoprotein (LDL) levels were elevated. In human aortic endothelial cells, exposure to LPS, oxidized LDL, and high glucose increased relative mtROS levels, which was effectively attenuated by MnSOD overexpression. MnSOD also suppressed intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression under these conditions.</p><p><strong>Innovation: </strong>Our findings demonstrate that endothelial-specific MnSOD overexpression suppresses obesity-related atherosclerosis in ApoE KO mice.</p><p><strong>Conclusion: </strong>mtROS plays a pivotal role in obesity-associated atherosclerosis, and targeting endothelial mtROS may offer a therapeutic strategy for preventing vascular complications in obesity. <i>Antioxid. Redox Signal.</i> 45, 63-77.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"63-77"},"PeriodicalIF":6.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox-Encoded Proteostasis: Heat Shock Proteins as Integrators of Stress Adaptation and Therapeutic Targets.","authors":"Kangmiao Guo, Xingyao Li, Qiwei Liang, Chaolei Chen, Jiaqi Lin, Tiancheng Zhan, Chengpeng Sun, Ning Kang, Feng Qiu, Qiang Zhang","doi":"10.1177/15230864261443823","DOIUrl":"10.1177/15230864261443823","url":null,"abstract":"<p><strong>Significance: </strong>Cellular proteostasis is essential for cellular proteome integrity, which is exquisitely sensitive to the redox environment. Heat shock proteins (HSPs) are the central chaperones that sense and adapt to these redox fluctuations. Emerging evidence demonstrates dysregulation of cellular HSPs-modulated redox-proteostasis in protein aggregation diseases, including cancers, senescence, neurodegenerative diseases, limb-girdle muscular dystrophy type D1, and β-thalassemia, making HSPs promising therapeutic targets in disease treatment.</p><p><strong>Recent advances: </strong>Redox post-translational modifications (PTMs) serve as master switchboards to dynamically modulate the structure and chaperone function of HSPs. Redox PTMs allow HSPs to participate in protein synthesis and folding, conformational maintenance, and degradation, thereby maintaining cellular proteostasis. Beyond their chaperone functions, HSPs also play critical roles in organelle-specific stress responses, such as mitochondrial unfolded protein response, endoplasmic reticulum (ER) stress, and unfolded protein response.</p><p><strong>Critical issues: </strong>Despite the well-known contributions of HSPs to redox-proteostasis, the double-edged functions of HSPs in protein aggregation diseases remain unclear. The main issues covered in this review include the regulation of HSPs by redox PTMs, the important role of HSPs in proteostasis and organelle-specific stress responses, dual modulation of HSPs in protein aggregation diseases, and pharmacological agents targeting HSPs.Further Directions:The functional diversity of HSPs in redox-proteostasis makes them promising therapeutic targets in disease treatment. Further studies should focus on exploiting agents that precisely target cysteine residues modifications on HSPs with good blood-brain barrier (BBB) penetration and low toxicity. <i>Antioxid. Redox Signal.</i> 45, 78-112.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"78-112"},"PeriodicalIF":6.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron Metabolism and Adipose Tissue Homeostasis: Emerging Perspectives for Obesity Intervention.","authors":"Beilei Wang, Xige Dong, Mengxu Sun, Yuanfen Xie, Ozioma Udochukwu Akakuru, Chunqin Li, Jiaxin Qin, Huanhuan Lv","doi":"10.1177/15230864261443818","DOIUrl":"10.1177/15230864261443818","url":null,"abstract":"<p><strong>Significance: </strong>The global obesity epidemic is a significant risk factor for chronic metabolic diseases. Iron, an essential micronutrient involved in numerous biological processes, exhibits a dual role in health and disease. Understanding the mechanistic interplay between iron metabolism and adipocytes is crucial for elucidating the pathogenesis of obesity.</p><p><strong>Recent advances: </strong>Emerging evidence indicates that iron plays a key role in adipose tissue physiology, and its dysregulation contributes substantially to obesity pathogenesis. Within adipocytes, iron exerts multifaceted effects, influencing lipid metabolism, differentiation, thermogenic capacity, secretory function, mitochondrial activity, and insulin sensitivity. Conversely, the metabolic status of adipose tissue reciprocally affects systemic iron homeostasis.Goal of Review:This review underscores the phenomenon of iron dysregulation in obesity. It examines the cellular mechanism describing iron demand and its dysregulation across adipose tissue subtypes. Following, it explores the functional pathology connecting iron imbalance to impaired energy metabolism, thermogenesis capacity, immune modulation, and secretion activity in adipose tissue, as well as iron-related oxidative stress, ferroptosis, heme toxicity, and cellular senescence within adipocytes in obesity. Then, it expands to the systemic level, highlighting the interorgan crosstalk in iron homeostasis, particularly among the liver, gut, and adipose tissue. Finally, it discusses the therapeutic strategies targeting iron homeostasis regulation to alleviate obesity and its related complications.</p><p><strong>Future direction: </strong>Despite advancements, questions remain regarding depot-specific iron regulation and its relationship with metabolic dysfunction. Future studies should employ tissue-specific genetic models, well-designed human trials, and multiomics approaches to establish causality and translate the findings into targeted iron-modulating therapies for obesity. <i>Antioxid. Redox Signal.</i> 45, 44-62.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"44-62"},"PeriodicalIF":6.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROCK Inhibition Reprograms Microglial Polarization to Promote Neuroprotection <i>via</i> NOX2/ROS/TXNIP Suppression.","authors":"Ziyu Wang, Xin Xu, Leshu Wang, Baoyun Guo, Falan Hu, Ziyan Li, Jinhua Chen, Jiyue Wen","doi":"10.1177/15230864261449244","DOIUrl":"10.1177/15230864261449244","url":null,"abstract":"<p><strong>Aim: </strong>Cerebral ischemia/reperfusion (I/R) injury represents a significant challenge to recanalization therapy for ischemic stroke and is critically influenced by microglial polarization. Although inhibition of Rho-associated protein kinase (ROCK) has been shown to mitigate cerebral I/R injury and associated neuroinflammation, its specific effect on the balance between M1 and M2 (anti-inflammatory) microglial polarization remains incompletely understood. This study aimed to elucidate the role and underlying mechanism of ROCK inhibition in regulating M1 and M2 microglial polarization, using the classical antidepressant fluoxetine as a positive control.</p><p><strong>Results: </strong>ROCK inhibitor fasudil and positive control fluoxetine effectively alleviated cerebral I/R injury and facilitated a shift in microglial polarization from the M1 to the M2 phenotype, both <i>in vivo</i> and <i>in vitro</i>. In the hippocampal tissues of cerebral I/R mice exposed to lipopolysaccharide, we observed an upregulation of thioredoxin-interacting protein (TXNIP) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2). ROCK2 knockdown promoted the M2 microglial polarization, suppressed the expression of NOX2 and TXNIP, and inhibited the activation of NF-κB P65 in mouse hippocampal tissue. Notably, pharmacological inhibition of NF-κB reduced the expression of NOX2 and TXNIP, as well as the production of reactive oxygen species (ROS), in microglia subjected to oxygen-glucose deprivation/reoxygenation. Correspondingly, inhibition of NOX2 also decreased TXNIP expression.Conclusion and Innovation:ROCK inhibition promotes a shift in microglial polarization from the M1 to the M2 subtype by suppressing the NF-κB/NOX2/ROS/TXNIP signaling pathway. This study provides the first evidence demonstrating the mechanism by which ROCK inhibition drives microglial polarization toward the M2 phenotype. <i>Antioxid. Redox Signal.</i> 45, 149-168.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"149-168"},"PeriodicalIF":6.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physalin A Restores Redox and Mitochondrial Homeostasis to Protect against Diabetic Retinopathy.","authors":"Yan-Ru Xiao, Yow-Wen Hsieh, Wei-Yong Lin, Yu-Sheng Hsieh, Wei-Cheng Jiang, Pei-Ying Pai, Yueh-Hsiung Kuo, Dah-Yuu Lu, Yu-Jung Lin, Wen-Tsong Hsieh","doi":"10.1177/15230864261442217","DOIUrl":"10.1177/15230864261442217","url":null,"abstract":"<p><strong>Aims: </strong>To determine whether physalin A (PA) safeguards the outer blood-retinal barrier under diabetic stress by engaging nuclear factor erythroid 2-related factor 2 (Nrf2) to restore redox balance and restrain ferroptosis in human retinal pigment epithelial (hRPE) cells and C57BLKS/J Iar -+Lepr^db/+Lepr^db mice.</p><p><strong>Results: </strong>In high-glucose challenged hRPE cells, PA dose-dependently preserved viability, maintained claudin-1/occludin/zonula occludens-1 abundance and membrane localization, and reversed ferroptosis hallmarks (restored solute carrier family 7 member 11 [SLC7A11], SLC3A2, and glutathione peroxidase 4; reduced ferrous iron [Fe²⁺] overload and lipid peroxidation). PA restored glutathione levels, reduced malondialdehyde (MDA), and enhanced the antioxidant defense pathway mediated by Nrf2, including upregulation of heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 2. Silencing Nrf2 abolished the effects of PA on barrier integrity and ferroptosis suppression, with rebounds in reactive oxygen species, MDA, Fe²⁺, and tight junction loss. In db/db mice treated systemically for 20 weeks, PA reduced Evans Blue leakage, increased retinal thickness, restored RPE tight junction proteins, and normalized mitochondrial architecture by transmission electron microscopy. PA rebalanced mitochondrial dynamics (dynamin 1-like, optic atrophy 1, fission 1, mitofusin 1, FUN14 domain containing 1), increased retinal mitochondrial DNA copy number, and partially stabilized glycemia and weight.</p><p><strong>Conclusion: </strong>PA restores redox tone, restrains ferroptosis, and preserves junctional integrity to protect the diabetic retina, with Nrf2 being indispensable for these benefits. These findings position PA as a promising adjunctive candidate for early diabetic retinopathy and support Nrf2-centered strategies to reinforce the outer blood-retinal barrier. <i>Antioxid. Redox Signal.</i> 45, 5-27.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"5-27"},"PeriodicalIF":6.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Citicoline Restores Endoplasmic Reticulum Homeostasis by Regulating Oxidative Stress Through CDO1 to Reverse Myopia Progression.","authors":"Peijuan Wu, Shan He, Li Zhang, Houli Li, Jiaxue Wu, Kun Yi, Qiuyun Sun, Ke Hu, Wenjuan Wan","doi":"10.1177/15230864261443857","DOIUrl":"10.1177/15230864261443857","url":null,"abstract":"<p><strong>Objective: </strong>To investigate whether citicoline alleviates endoplasmic reticulum (ER) stress by modulating oxidative stress in myopia.</p><p><strong>Results: </strong>A form-deprivation myopia model in guinea pigs and a hypoxia-induced model in human scleral fibroblasts revealed that citicoline downregulated cysteine dioxygenase 1 (CDO1) expression, increased glutathione, and reduced reactive oxygen species. These changes mitigated oxidative stress, suppressed ER stress, maintained cellular homeostasis, and inhibited extracellular matrix remodeling, leading to reduced axial elongation.</p><p><strong>Innovation: </strong>Transcriptomic profiling identified CDO1 as a novel downstream effector of citicoline, linking cysteine metabolism to oxidative and ER stress regulation in myopia.</p><p><strong>Conclusion: </strong>Citicoline shows potential to delay myopia progression by alleviating ER stress through CDO1-mediated redox regulation, providing preclinical mechanistic insight into its possible role in myopia control. <i>Antioxid. Redox Signal.</i> 45, 113-132.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"113-132"},"PeriodicalIF":6.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}