Jiasheng Ju , Chunchao Cheng , Longtao Cui , Biao Hong, Qi Zhan, Qixue Wang, Xiaoteng Cui, Dongyuan Su, Yanping Huang, Chunsheng Kang
{"title":"EPIC-1042 alleviates cerebral ischemic/reperfusion injury through TAX1BP1-induced mitophagy","authors":"Jiasheng Ju , Chunchao Cheng , Longtao Cui , Biao Hong, Qi Zhan, Qixue Wang, Xiaoteng Cui, Dongyuan Su, Yanping Huang, Chunsheng Kang","doi":"10.1016/j.freeradbiomed.2025.03.023","DOIUrl":"10.1016/j.freeradbiomed.2025.03.023","url":null,"abstract":"<div><div>Post ischemia-reperfusion (I/R) injury, an upregulation in Polymerase I and transcript release factor (PTRF) expression is observed. PTRF is implicated in the regulation of various cellular processes within neuronal cells, thereby exacerbating the deleterious effects of I/R injury. EPIC-1042 is a small molecule pharmacological agent that exhibits specificity in binding to PTRF. Therefore, this study aimed to explore whether EPIC-1042 could be used as a treatment for I/R injury. To achieve this goal, we observed brain injury in mice following EPIC-1042 pre-administration, and then transitioned to therapeutic administration. After observing the pre-protective and therapeutic effects of the drug, proteomic analysis revealed that the expression of TAX1BP1 continued to decline in a time-dependent manner, while EPIC-1042 was able to inhibit this decline. However, the function of TAX1BP1 in ischemic stroke is not yet fully understood. Subsequent experiments confirmed that the addition of EPIC-1042 resulted in an enhancement of mitophagy. Silencing the expression of TAX1BP1 abrogated the drug's effects, indicating that EPIC-1042 exerts a protective function by promoting mitophagy via TAX1BP1 mediation. We further investigated the synergistic effects of EPIC-1042 and edaravone by administering the two drugs in combination, observing an enhanced therapeutic efficacy compared to the administration of each drug alone. Subsequently, we optimized the administration protocol for the two drugs by utilizing liposome encapsulation for both drugs. This approach enabled us to achieve significant therapeutic outcomes while reducing both the dosage and frequency of administration, thereby demonstrating the potential for clinical translation of EPIC-1042.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 367-381"},"PeriodicalIF":7.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662937","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":"The two faces of coenzyme A in cellular biology","authors":"Charlie Brett, Ivan Gout","doi":"10.1016/j.freeradbiomed.2025.03.025","DOIUrl":"10.1016/j.freeradbiomed.2025.03.025","url":null,"abstract":"<div><div>Coenzyme A (CoA) is an essential cofactor present in all living cells, which plays critical roles in diverse biochemical processes, including cellular metabolism, signal transduction, regulation of gene expression, and the antioxidant response. This review summarizes current knowledge on the role of CoA and its metabolically active thioesters in promoting cellular growth and proliferation (pro-growth) and discusses emerging research on CoA's antioxidant properties that enhance cell survival (pro-survival).</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 162-173"},"PeriodicalIF":7.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663078","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}
Yuqin Zhang , Yonghua Ye , Yi Feng , Xuezhen Li , Lingxuan Chen , Xiaoxue Zou , Guohong Yan , Yaping Chen , Lihong Nan , Wei Xu , Lixia Chen , Hua Li
{"title":"Kirenol alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the CK2/AKT pathway","authors":"Yuqin Zhang , Yonghua Ye , Yi Feng , Xuezhen Li , Lingxuan Chen , Xiaoxue Zou , Guohong Yan , Yaping Chen , Lihong Nan , Wei Xu , Lixia Chen , Hua Li","doi":"10.1016/j.freeradbiomed.2025.03.022","DOIUrl":"10.1016/j.freeradbiomed.2025.03.022","url":null,"abstract":"<div><div>Ischemic stroke represents a predominant cause of morbidity and mortality globally, resulting from abrupt vascular occlusion or rupture, which precipitates considerable neuronal damage. This study aims to shed more light on the specific neuroprotective mechanisms of Kirenol, a bioactive diterpene derived from traditional herbal medicine, with a particular focus on its regulation of mitochondrial dynamics via the CK2/AKT signalling pathway and its impact on the mitochondrial fusion protein Optic atrophy 1 (Opa1). The effects of Kirenol on neuronal viability, mitochondrial function, and pertinent signalling pathways were evaluated by employing a middle cerebral artery occlusion (MCAO) model in rats and subjecting HT22 neuronal cells to oxidative stress. Treatment with Kirenol significantly improved neurological outcomes, augmented Opa1 expression, and restored apoptotic-related protein markers, antioxidative factors, mitochondrial membrane potential, and adenosine triphosphate (ATP) levels (<em>P</em> < 0.01). Mechanistically, Kirenol elevated CK2 levels and phosphorylated AKT while inhibiting CK2/AKT signalling attenuated Kirenol's protective effects on Opa1 expression. Furthermore, silencing Opa1 using siRNA diminished the neuroprotective effects of Kirenol on oxidative stress and apoptosis-related markers, underscoring the critical role of Opa1. <em>In vitro</em> assessments demonstrated that Kirenol effectively mitigated oxidative stress-induced neuronal damage, restoring cell morphology and viability. Kirenol exhibited dose-dependent neuroprotective effects in the MCAO model (<em>P</em> < 0.01). These findings elucidate the neuroprotective role of Kirenol in ischemic stroke through Opa1-mediated mitochondrial fusion and highlight the CK2/AKT pathway as a promising therapeutic target.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 353-366"},"PeriodicalIF":7.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639503","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}
Hwa-Young Lee, Hafiz Maher Ali Zeeshan, Hyung-Ryong Kim, Han-Jung Chae
{"title":"Corrigendum to \"Nox 4 regulates the eNOS uncoupling process in aging endothelial cells\" [Free Rad. Biol. Med. 113 (2017) 26-35].","authors":"Hwa-Young Lee, Hafiz Maher Ali Zeeshan, Hyung-Ryong Kim, Han-Jung Chae","doi":"10.1016/j.freeradbiomed.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.001","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633871","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":"Dried blood spot analysis of long-chain polyunsaturated fatty acids and oxylipins for monitoring heart failure","authors":"Denise Biagini , Giulia Bertazzo , Silvia Ghimenti , Alessio Lenzi , Camille Oger , Jean-Marie Galano , Laurence Balas , Thierry Durand , Nicola Riccardo Pugliese , Silvia Armenia , Stefano Masi , Fabio Di Francesco , Tommaso Lomonaco","doi":"10.1016/j.freeradbiomed.2025.03.020","DOIUrl":"10.1016/j.freeradbiomed.2025.03.020","url":null,"abstract":"<div><div>Heart failure (HF) occurs when the heart fails to meet the body's demands. Differentiating and managing HF with Preserved Ejection Fraction (HFpEF) versus Reduced Ejection Fraction (HFrEF) remains challenging, as therapeutic strategies for HFpEF have largely been ineffective. Exercise intolerance is a hallmark of HFpEF, making the identification of biological pathways underlying exercise-related impairments particularly important.</div><div>In this study, we integrated cardiopulmonary exercise testing with exercise stress echocardiography (CPET-ESE) and MS-based targeted lipid and epilipid profiling to investigate metabolic and immune dysregulation across different stages of HF. Due to the technical challenges and patient discomfort associated with venous blood collection during exercise, we employed a less invasive Dried Blood Spot (DBS) approach.</div><div>For the first time, we successfully validated a method for targeted profiling of 52 oxylipins and 4 PUFAs in DBS samples, covering the entire inflammatory cascade. We established reliable DBS handling and storage procedures, with the addition of an internal standard mixture on filter paper ensuring high analyte recovery (93–107 %) and precision (RSD ≤12 %). Data from HF patients revealed significant differences in AA and anti-inflammatory omega-3 PUFA levels at rest. Furthermore, measuring AA and its epoxide metabolite, 8,9-EET, during exercise enabled clear differentiation between HFpEF, HFrEF, and stage A-B patients, potentially supporting earlier and more accurate diagnosis. Profiling alterations in free fatty acids and oxylipins could serve as a valuable tool for the in-depth pathophysiological characterization of HF patients.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 13-23"},"PeriodicalIF":7.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639492","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}
Jie Liu , Luyao Deng , Bingyi Yao , Yuanjin Zhang, Junze Huang, Shengbo Huang, Chenmeizi Liang, Yifei Shen, Xin Wang
{"title":"Carboxylesterase 2A gene knockout or enzyme inhibition alleviates steatohepatitis in rats by regulating PPARγ and endoplasmic reticulum stress","authors":"Jie Liu , Luyao Deng , Bingyi Yao , Yuanjin Zhang, Junze Huang, Shengbo Huang, Chenmeizi Liang, Yifei Shen, Xin Wang","doi":"10.1016/j.freeradbiomed.2025.03.021","DOIUrl":"10.1016/j.freeradbiomed.2025.03.021","url":null,"abstract":"<div><div>Metabolic dysfunction associated steatotic liver disease (MASLD) is a widespread liver disease that progresses from simple steatosis to severe steatohepatitis stage. Despite the recognized importance of carboxylesterase 2 (CES2) in hepatic lipid metabolism, the role of CES2 in hepatic inflammation remains unclear. The rat genome encodes six <em>Ces2</em> genes and <em>Ces2a</em> shows high expression in the liver and intestine. Lipid metabolism, inflammation, fibrosis, and endoplasmic reticulum (ER) stress were investigated in <em>Ces2a</em> knockout (KO) rats. KO rats showed spontaneous liver lipid accumulation due to increased lipogenesis and reduced fatty acid oxidation. Non-targeted lipidomic analysis revealed enhanced lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) in KO rats and increased concentrations of ligands, thus activating the expression of PPARγ. Although there was simple lipid accumulation in the liver of KO rats, <em>Ces2a</em> deficiency showed a significant protective effect against LPS and diet-induced hepatic steatohepatitis by inhibiting ER stress regulated by PPARγ activation. In line with this, treatment with tanshinone IIA, a CES2 inhibitor, significantly alleviated the progression of steatohepatitis induced by the MCD diet. In conclusion, the increased PPARγ expression in <em>Ces2a</em> deficiency may counteract liver inflammation and ER stress despite the presence of simple steatosis. Therefore, CES2 inhibition represents a potential therapeutic approach for steatohepatitis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 279-291"},"PeriodicalIF":7.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633870","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}
Wenyue Yang , Zhou Zhu , Chaohua Zhou , Junhui Chen , Jinhuan Ou , Haibo Tong , Ashok Iyaswamy , Peng Chen , Xu Wei , Chuanbin Yang , Wei Xiao , Jigang Wang , Wei Zhang
{"title":"The rheumatoid arthritis drug Auranofin targets peroxiredoxin 1 and peroxiredoxin 2 to trigger ROS-endoplasmic reticulum stress axis-mediated cell death and cytoprotective autophagy","authors":"Wenyue Yang , Zhou Zhu , Chaohua Zhou , Junhui Chen , Jinhuan Ou , Haibo Tong , Ashok Iyaswamy , Peng Chen , Xu Wei , Chuanbin Yang , Wei Xiao , Jigang Wang , Wei Zhang","doi":"10.1016/j.freeradbiomed.2025.03.016","DOIUrl":"10.1016/j.freeradbiomed.2025.03.016","url":null,"abstract":"<div><div>Auranofin (AF) is a gold-based compound and it has been used in the treatment of rheumatoid arthritis for over four decades. Recently, it has been demonstrated to show significant antitumor activity across various cancer types and is being repurposed as an anticancer drug. However, the precise mechanisms underlying its antitumor effects, particularly its binding targets, remain poorly understood. Here, we demonstrate that Auranofin (AF) exerts cytotoxic effects in 786-O renal cancer cells via inducing apoptosis. Mechanistic studies reveal that AF induces reactive oxygen species (ROS) accumulation, which is a key factor in mediating AF-induced stress and subsequently apoptosis. Notably, both ROS and ER stress induce autophagy, and inhibition of autophagy further enhances AF-induced cytotoxicity. Interestingly, activity-based protein profiling (ABPP) analysis identifies two key antioxidant enzymes, peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2), as direct binding targets of AF. Importantly, overexpression of PRDX1 or PRDX2 inhibits AF-induced ROS accumulation and subsequent apoptosis. Overall, our findings demonstrate that AF induces apoptosis by covalently binding to PRDX1/2 to inhibit its activity, leading to ROS accumulation, which triggers ER stress and apoptosis. At the same time, ER stress triggers a cytoprotective autophagic response. These findings provide novel insights into the mechanism of AF-induced cytotoxicity and suggest PRDX1/2 as critical targets for the development of anti-renal cancer therapies.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 1-12"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633889","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}
Qiangde Liu , Xiao Tang , Bingyuan Yang , Tingting Hao , Shangzhe Han , Xiang Xu , Zengqi Zhao , Wencong Lai , Yueru Li , Jianlong Du , Kangsen Mai , Qinghui Ai
{"title":"Autophagy and endoplasmic reticulum stress-related protein homeostasis links palmitic acid to hepatic lipotoxicity in zebrafish (Danio rerio), counteracted by linoleic acid","authors":"Qiangde Liu , Xiao Tang , Bingyuan Yang , Tingting Hao , Shangzhe Han , Xiang Xu , Zengqi Zhao , Wencong Lai , Yueru Li , Jianlong Du , Kangsen Mai , Qinghui Ai","doi":"10.1016/j.freeradbiomed.2025.03.018","DOIUrl":"10.1016/j.freeradbiomed.2025.03.018","url":null,"abstract":"<div><div>Saturated fatty acids (SFAs) are the primary contributors to hepatic lipotoxic injuries accompanied by the accumulation of hepatic insoluble protein inclusions that are composed of ubiquitinated proteins and p62, but the role of these inclusions in the SFA-induced hepatic lipotoxic injuries and their regulatory mechanisms are incompletely understood. In this study, we demonstrated that palmitic acid (PA), a dietary SFA, induced aberrant accumulation of hepatic insoluble protein inclusions, leading to hepatic lipotoxic injuries in zebrafish. Mechanistically, the accumulation of hepatic insoluble protein inclusions and the subsequent lipotoxic injuries induced by PA were attributed to reduced autophagy activity and increased endoplasmic reticulum (ER) stress. In addition, the upregulation of <em>p6</em>2 by the ER stress response factor XBP1s and ATF4 further exacerbated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries. Importantly, the ω-6 PUFA linoleic acid (LA) attenuated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries by improving defective autophagy and reducing ER stress induced by PA. Overall, the present study provides new mechanisms by which SFAs and ω-6 PUFA influence hepatic lipotoxic injuries. These findings not only advance the understanding of hepatic lipotoxic injuries induced by SFAs, but also provide new insights for optimizing the rational substitution of fish oil by vegetable oils in aquaculture and the balance of fatty acid intake in human diets.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 148-161"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633867","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}
Jia-Zih Dai , Wen-Jing Hsu , Mei-Hsiang Lin , Pei-Wei Shueng , Chi-Ching Lee , Ching-Chieh Yang , Cheng-Wei Lin
{"title":"YAP-mediated DDX3X confers resistance to ferroptosis in breast cancer cells by reducing lipid peroxidation","authors":"Jia-Zih Dai , Wen-Jing Hsu , Mei-Hsiang Lin , Pei-Wei Shueng , Chi-Ching Lee , Ching-Chieh Yang , Cheng-Wei Lin","doi":"10.1016/j.freeradbiomed.2025.03.019","DOIUrl":"10.1016/j.freeradbiomed.2025.03.019","url":null,"abstract":"<div><div>Metabolic shifts in cancer cells were found to participate in tumorigenesis, especially driving chemotherapeutic resistance. Ferroptosis is a newly discovered form of cell death induced by excessive accumulations of iron and lipid peroxidation. Susceptibility to ferroptosis can be intrinsically regulated by various cellular metabolic pathways. Therefore, inducing ferroptosis might be a promising anticancer therapeutic strategy. DEAD-box helicase 3 X-linked (DDX3X), a critical modulator of RNA metabolism, was identified as an oncogene in breast cancer and also participates in cancer metabolism and chemotherapeutic resistance. However, the molecular regulation of the association between DDX3X and ferroptosis is largely unknown. Herein, we investigated the correlation between resistance to ferroptosis and DDX3X expression in breast cancer cells. We found that elevation of DDX3X was associated with increased resistance to a ferroptosis inducer in breast cancer cells, and manipulating DDX3X expression regulated the sensitivity to the ferroptosis inducer. Importantly, DDX3X upregulated expression of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4) gene to confer ferroptosis resistance in breast cancer cells. Moreover, DDX3X was transcriptionally upregulated by the yes-associated protein (YAP). Knockdown of YAP downregulated DDX3X mRNA expression and facilitated lipid peroxidation, but that were restored in the presence of DDX3X. Clinically, coexpression of DDX3X and YAP was found in a variety of malignancy, and their elevation conferred poor survival prognosis in patients with breast cancer. Together, our findings reveal the crucial role of DDX3X in sensitivity to ferroptosis and underscore its potential as a diagnostic marker and therapeutic target. DDX3X renders resistance to ferroptosis and plays a role in mitigating lipid peroxidation, paving the way for therapeutic vulnerability via targeting cancer metabolism.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 330-339"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633892","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}
Min-Min Cao , Zhe Guo , Jun Wang , Hui-Yong Ma , Xiao-Yan Qin , Yang Hu , Rongfeng Lan
{"title":"Astragalin alleviates lipopolysaccharide-induced depressive-like behavior in mice by preserving blood-brain barrier integrity and suppressing neuroinflammation","authors":"Min-Min Cao , Zhe Guo , Jun Wang , Hui-Yong Ma , Xiao-Yan Qin , Yang Hu , Rongfeng Lan","doi":"10.1016/j.freeradbiomed.2025.03.014","DOIUrl":"10.1016/j.freeradbiomed.2025.03.014","url":null,"abstract":"<div><div>Astragalin (AST) is a flavonoid glycoside commonly found in edible plants and medicinal herbs with a variety of therapeutic effects. This study aimed to investigate whether AST protects the integrity of the blood-brain barrier (BBB) and inhibits neuroinflammation, thereby alleviating depressive-like behaviors. LPS-stimulated cultured cells and LPS-induced BBB disruption and depressive-like behavior mice models were employed. We founded that AST inhibited LPS-induced inflammatory responses in microglial BV2 cells and protected SH-SY5Y cells from inflammatory injury. In mice, AST effectively ameliorated LPS-induced depressive-like behaviors, which was attributed to its ability to maintain BBB integrity and inhibit inflammatory damage caused by LPS invasion. Furthermore, AST suppressed LPS-induced activation of glial cells, protecting neuronal dendritic spines, synapses, and mitochondria from inflammatory damage. It also reduced the elevation of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, and normalized the aberrant activation of inflammatory signaling pathways, including RIPK1/RIPK3/MLKL and mTOR/NF-κB. In conclusion, AST protects BBB integrity and brain tissue from inflammatory damage, offering new insights for drug development and clinical interventions in systemic inflammatory responses, such as sepsis-induced encephalitis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 340-352"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633866","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}