Free Radical Biology and Medicine最新文献

{"title":"Metabolic reprogramming and astrocytes polarization following ischemic stroke.","authors":"Weizhuo Lu, Jiyue Wen","doi":"10.1016/j.freeradbiomed.2025.01.002","DOIUrl":"10.1016/j.freeradbiomed.2025.01.002","url":null,"abstract":"<p><p>Astrocytes are critical for maintaining neuronal activity. Activation of astrocytes, occurs within minutes from ischemic stroke onset due to ischemic causes and subsequent inflammatory damage. Activated astrocytes, also known as reactive astrocytes, are divided into two different phenotypes: A1 (pro-inflammatory) and A2 (anti-inflammatory) astrocytes. A2 astrocytes support neuronal survival and promote tissue healing, while A1 astrocytes have neurotoxic effects. Thus, polarization of reactive astrocyte into A1 or A2 genotype is closely correlated with the development of cerebral ischemia/reperfusion (I/R) injury. Metabolic reprogramming is a process that various metabolic pathways upregulate in cells to balance energy, alter their phenotype, and produce building-block requirements. A1 and A2 astrocytes display different metabolic reprogramming, such as glycolysis, glutamate uptake, and glycogenolysis. Accumulating evidence suggested that manipulation of energy metabolism homeostasis can induce astrocytes to switch from A1 to A2 phenotype. This review disucss the potential factors in affecting astrocytic polarization, emphasizes metabolic reprogramming in reactive astrocytes within the pathophysiological context of cerebral I/R, and explores the relationship between metabolic reprogramming and astrocytic polarization. Importantly, we reveal that regulating metabolic reprogramming in reactive astrocytes may be a potential therapeutic target for cerebral I/R injury.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"197-206"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931132","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":"E-cigarette-induced changes in cell stress and mitochondrial function.","authors":"Ramamurthy Chitteti, Juan Pablo Zuniga-Hertz, Jorge A Masso-Silva, John Shin, Ingrid Niesman, Christine M Bojanowski, Avnee J Kumar, Mark Hepokoski, Laura E Crotty Alexander, Hemal H Patel, David M Roth","doi":"10.1016/j.freeradbiomed.2025.01.004","DOIUrl":"10.1016/j.freeradbiomed.2025.01.004","url":null,"abstract":"<p><p>Inhaling aerosols from electronic nicotine delivery systems, such as e-cigarettes (e-cigs), may pose health risks beyond those caused by nicotine intake. Exposure to e-cig aerosols can lead to the release of exosomes and metabolites into the bloodstream, potentially affecting mitochondrial physiology across the body, leading to chronic inflammatory diseases. In this study we assessed the effects of e-cig use by young healthy human subjects on the circulating exosome profile and markers of cell stress, and also defined the effects of e-cig user plasma on mitochondrial function in endothelial cells (EA. Hy 926) and epithelial cells (A549) via adoptive transfer. E-cig users had altered plasma exosome profiles, with significantly increased levels of cell free mitochondrial DNA (mtDNA), protein carbonyls, and 4-HNE relative to non-users. Plasma from e-cig users decreased maximal mitochondrial respiration and spare capacity of cells, while also increasing metabolic stress, as evidenced by changes in mitochondrial phenotype from basal to stressed in both endothelial and epithelial cells, which was corroborated by electron microscopy demonstrating structural changes in mitochondria. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels significantly increased in e-cig plasma-subjected cells. Overall, we identified alterations in plasma exosome profiles and increased markers of mitochondrial stress in e-cig users and evidence that circulating factors within plasma from e-cig users drives metabolic stress in endothelial and epithelial cells. Our results imply that e-cig use adversely affects mitochondrial function, leading to stress and potentially chronic inflammation across the body.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"329-338"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931131","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":"Targeted mitochondrial function for cardiac fibrosis: An epigenetic perspective.","authors":"Peng Liu, Zhen-Yu Liu, Sui Mao, Xin-Yu Shen, Zhi-Yan Liu, Li-Chan Lin, Jing-Jing Yang, Ye Zhang, Jian-Yuan Zhao, Hui Tao","doi":"10.1016/j.freeradbiomed.2025.01.001","DOIUrl":"10.1016/j.freeradbiomed.2025.01.001","url":null,"abstract":"<p><p>Mitochondria, commonly referred to as \"energy factories\"of cells, play a crucial role in the function and survival of cardiomyocytes. However, as research on cardiac fibrosis has advanced, mitochondrial dysfunction(including changes in energy metabolism, calcium ion imbalance, increased oxidative stress, and apoptosis)is now recognized as a significant pathophysiological pathway involved in cardiac remodeling and progression, which also negatively affects the function and structure of the heart. In recent years, research focusing on targeting mitochondria has gained significant attention, offering new approaches for treating cardiac fibrosis. Targeted mitochondrial therapy for cardiac fibrosis represents an emerging therapeutic strategy that aims to inhibit cardiac fibroblast proliferation or protect cardiomyocytes from damage by enhancing mitochondrial function. However, current research on epigenetic treatments for cardiac fibrosis through mitochondrial targeting remains limited. This review explores the relationship between mitochondrial dysfunction and cardiac fibrosis, as well as the epigenetic regulatory mechanisms involved in targeted mitochondrial therapy for cardiac fibrosis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"163-172"},"PeriodicalIF":7.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926803","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 role of skeletal muscle respiratory capacity in exercise performance.","authors":"Pablo M Garcia-Roves, Jorge Alvarez-Luis, Sandra Cutanda-Tesouro","doi":"10.1016/j.freeradbiomed.2024.12.060","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2024.12.060","url":null,"abstract":"<p><p>The connection between the respiratory capacity of skeletal muscle mitochondria and athletic performance is widely acknowledged in contemporary research. Building on a solid foundation of prior studies, current research has fostered an environment where scientists can effectively demonstrate how a tailored regimen of exercise intensity, duration, and frequency significantly boosts mitochondrial function within skeletal muscles. The range of exercise modalities is broad, spanning from endurance and high-intensity interval training to resistance-based exercises, allowing for an in-depth exploration of effective strategies to enhance mitochondrial respiratory capacity-a key factor in improving exercise performance, in other words offering a better skeletal muscle capacity to cope with exercise demands. By identifying optimal training strategies, individuals can significantly improve their performance, leading to better outcomes in their fitness and athletic endeavours. This review provides the prevailing insights on skeletal muscle mitochondrial respiratory capacity and its role in exercise performance, covering essential instrumental and methodological aspects, findings from animal studies, potential sex differences, a review of existing human studies, and considerations for future research directions.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926806","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":"Ginsenoside Rd alleviates early brain injury by inhibiting ferroptosis through cGAS/STING/DHODH pathway after subarachnoid hemorrhage.","authors":"Guang-You Jiang, Hong-Rui Yang, Chen Li, Nan Liu, Sheng-Ji Ma, Bing-Xuan Jin, Cong Yan, Hai-Dong Gong, Ji-Yi Li, Hao-Chen Yan, Guang-Xi Ye, Wen-Yu Wang, Cheng Gao","doi":"10.1016/j.freeradbiomed.2024.12.058","DOIUrl":"10.1016/j.freeradbiomed.2024.12.058","url":null,"abstract":"<p><p>Ferroptosis, a recently identified form of regulated cell death, is characterized by lipid peroxidation and iron accumulation, plays a critical role in early brain injury after subarachnoid hemorrhage. Ginsenoside Rd, an active compound isolated from ginseng, is known for its neuroprotective properties. However, its influence on SAH-induced ferroptosis remains unclear. In this study, we constructed an SAH model using intravascular perforation in vivo and treated HT22 cells with oxyhemoglobin to simulate the condition in vitro. We observed significant changes in ferroptosis markers, including GPX4 and ACSL4, following SAH. Administration of ginsenoside Rd to both rats and HT22 cells effectively inhibited neuronal ferroptosis induced by SAH, alleviating neurological deficits and cognitive dysfunction in rats. Notably, the neuroprotective properties of ginsenoside Rd were countered by the STING pathway agonist 2'3'-cGAMP. Experiments conducted in vitro and in vivo illustrated that the impacts of ginsenoside Rd were counteracted by the BQR inhibitor. Our findings suggest that ginsenoside Rd mitigates EBI after SAH by suppressing neuronal ferroptosis through the cGAS/STING pathway while upregulating DHODH levels. These outcomes emphasize the potential of ginsenoside Rd as a therapeutic candidate for subarachnoid hemorrhage.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"299-318"},"PeriodicalIF":7.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921086","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":"Ethanolic extract of Akhuni induces ROS-mediated apoptosis through ERK and AKT signalling pathways: Insights from metabolic profiling and molecular docking studies.","authors":"Deep Jyoti Das, Dipankar Barman, Vanlalhruaii Famhawite, Jyoti Lakshmi Hati Boruah, Amit Kumar Pathak, K Nusalu Puro, Rinku Baishya","doi":"10.1016/j.freeradbiomed.2024.12.059","DOIUrl":"10.1016/j.freeradbiomed.2024.12.059","url":null,"abstract":"<p><p>Akhuni, an ethnic food of northeast India, induces ROS-mediated apoptosis in cancer cells. This is the first report on the anticancer potential of Akhuni. Akhuni is a traditional fermented soybean product known for its umami taste and delicacy, commonly used in Northeast India's cuisine. The current work demonstrates the antiproliferative potential of Akhuni ethanolic extract (AKET) against B16-F10 and MDA-MB-231 cancer cells and its mechanism of action supported by metabolic profiling and molecular docking. The investigation evaluated cytotoxicity, cell cycle distribution, caspase activity, apoptosis-related gene and protein expression, and oxidative stress imposed by excess reactive oxygen species (ROS) in both cell types. Phytochemical characterization of AKET was performed using HPLC. The growth of both cells is concentration-dependently inhibited after AKET treatment in MTT and flow cytometry experiments, leading to an arrest in the cell cycle at the G2 phase. Intracellular ROS levels increased in response to AKET treatment, suggesting that ROS in both cells triggered the mitochondrial pathway. Compared to the untreated cells, qRT-PCR analysis showed that AKET significantly reduced Cdk2 and Bcl-2 and increased the mRNA expression levels of Caspase-9, Bax, FasL, and Bid. Additionally, Caspase-8, Caspase-3, and the protein p53 were significantly upregulated in AKET-treated cells, as confirmed by both real-time and ELISA assays. In both the B16-F10 and MDA-MB-231 cell lines, the Western blot analysis showed that AKET caused an elevation of the expression of the Bax protein and downregulation of the Erk1/2, Akt, and Bcl2 proteins. Six isoflavones were identified from AKET through HPLC analysis. Molecular docking results indicate compounds in the AKET extract like daidzein, genistein and glycitein act as potent inhibitors of the key oncoprotein, AKT. These findings suggest that AKET has an anticancer effect through ROS-mediated ERK1/2 and AKT signalling pathways.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"137-149"},"PeriodicalIF":7.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921085","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":"Electronic cigarette vape decreases nitric oxide bioavailability in vascular smooth muscle cells via increased cytoglobin-mediated metabolism.","authors":"Elsayed M Mahgoup, Sahar A Khaleel, Mohamed A El-Mahdy, Jay L Zweier","doi":"10.1016/j.freeradbiomed.2024.12.057","DOIUrl":"10.1016/j.freeradbiomed.2024.12.057","url":null,"abstract":"<p><p>Cytoglobin (Cygb) regulates vascular tone by modulating nitric oxide (NO) metabolism in vascular smooth muscle cells (VSMCs). In the presence of its cytochrome B5a (B5)/B5 reductase-isoform-3 (B5R) reducing system, Cygb controls NO metabolism via oxygen-dependent NO dioxygenation. Electronic cigarette (EC) use has been shown to induce vascular dysfunction and decrease NO bioavailability; however, the role of Cygb-mediated NO metabolism in the pathophysiology of this process has not been previously investigated. Therefore, we utilized aortic VSMCs with EC vape extract (ECE) exposure to elucidate the effects of EC vape constituents on NO degradation and alterations in the process of Cygb-mediated NO metabolism. VSMCs were exposed to ECE, either nicotine-free (ECEV) or nicotine-containing (ECEN), for various durations. NO decay rates were measured along with cellular expression of Cygb and its B5/B5R reducing system. Exposure to ECEV led to a much higher rate of NO consumption by VSMCs, with an even larger effect following ECEN exposure. With 4 h of exposure, a modest increase in NO decay rate occurred that was followed by much higher increases with exposure times of 24-48 h. This effect was paralleled by upregulation of Cygb and B5/B5R expression. siRNA-mediated knock-down of Cygb expression largely reversed this ECE-induced increase in NO metabolism rate. Thus, ECE exposure led to increased Cygb-mediated NO metabolism in VSMCs with diminished NO bioavailability, which in turn can play a key role in EC-induced vascular dysfunction.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"339-349"},"PeriodicalIF":7.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913124","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":"Sulfonated albumin from hepatocytes accelerates liver fibrosis in nonalcoholic fatty liver disease through endoplasmic reticulum stress.","authors":"Tiantian Liu, Minghao Sui, Miaomiao Tian, Nijin Wu, Songbo Zhao, Yingchun Wang, Yinuo Yang, Shujun Ma, Deyan Jiao, Le Wang, Yuemin Feng, Yahui Zhang, Chengyong Qin, Chenxi Liu, Jianni Qi, Qiang Zhu","doi":"10.1016/j.freeradbiomed.2024.12.055","DOIUrl":"10.1016/j.freeradbiomed.2024.12.055","url":null,"abstract":"<p><strong>Background: </strong>Posttranslational modifications (PTM) of albumin occur in liver diseases; however, little is known about the source and function of sulfonated albumin, a significant modification of albumin occurring in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the mechanism underlying sulfonated albumin production and its role in the progression of NAFLD-related liver fibrosis.</p><p><strong>Methods: </strong>Serum samples from healthy controls and patients with NAFLD were used to measure the proportion of sulfonated albumin. Mice models with NAFLD fed with high-fat diet (HFD) and methionine choline-deficient diet (MCD) were constructed. RNA sequencing, KEGG analysis, and GSEA were used to explore the mechanism of sulfonated albumin production and its mechanism of activating hepatic stellate cells (HSCs) and promoting the progression of liver fibrosis in NAFLD.</p><p><strong>Results: </strong>Sulfonated albumin levels increased significantly in both human and mouse NAFLD serum samples. In vivo studies in mice have shown that the intraperitoneal injection of sulfonated albumin promotes inflammation, hepatic steatosis, and liver fibrosis in NAFLD. In addition, autophagy has been verified as a key mechanism in the regulation of sulfonated albumin production. We also demonstrated that reactive oxygen species (ROS) production depends on the accumulation of damaged mitochondria and affects the production of sulfonated albumin under the regulation of autophagy. Hepatocyte-derived sulfonated albumin activates HSCs through the GAL3 receptor, thereby activating the endoplasmic reticulum (ER) stress pathway and promoting profibrotic activation of HSCs.</p><p><strong>Conclusions: </strong>Our study demonstrated that sulfonated albumin activated HSCs through GAL3, thereby accelerating NAFLD-related liver fibrosis. Serum sulfonated albumin may be a potential diagnostic marker for liver fibrosis and an important target for the treatment of NAFLD-related liver fibrosis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"150-162"},"PeriodicalIF":7.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913558","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":"Peroxynitrite is involved in the mitochondrial dysfunction induced by Sorafenib in liver cancer cells.","authors":"Patricia de la Cruz-Ojeda, Elena Navarro-Villarán, Marina Fuertes-Agudo, Ana Mata, Guillermo López-Lluch, Plácido Navas, Susana Cadenas, Marta Casado, Jordi Muntané","doi":"10.1016/j.freeradbiomed.2024.12.053","DOIUrl":"10.1016/j.freeradbiomed.2024.12.053","url":null,"abstract":"<p><strong>Background: </strong>Sorafenib is a tyrosine kinase inhibitor (TKI) that belongs to the landscape of treatments for advanced stages of hepatocellular carcinoma (HCC). The induction of cell death and cell cycle arrest by Sorafenib has been associated with mitochondrial dysfunction in liver cancer cells. Our research aim was to decipher underlying oxidative and nitrosative stress induced by Sorafenib leading to mitochondrial dysfunction in liver cancer cells.</p><p><strong>Methods: </strong>MnTBAP, catalase and the scavenger of peroxynitrite FeTPPs were administered to Sorafenib (0-10 μM)-treated HepG2 cells. Oxygen consumption and glycolytic flux were determined in cultured cells. Mitochondrial complex activities were measured in mitochondrial fraction and cell lysates. The protein and mRNA expression of subunits of electron transport chain (ETC) were assessed by immunoblot and RNA-seq.</p><p><strong>Results: </strong>Sorafenib (10 μM) increased nitric oxide (NO) and superoxide anion (O₂^.-) leading to peroxynitrite generation, and drastically reduced oxygen consumption. Moreover, Sorafenib led to mitochondrial network disorganization and loss of membrane potential. The administration of FeTPPs influenced the recovery of mitochondrial network and oxygen consumption, as well as associated ATP production. Sorafenib downregulated the mRNA expression of all mitochondrial-encoded subunits of ETC and, at to a lesser extent, nuclear-encoded mitochondrial genes. The protein expression of complex I, complex III and complex IV was greatly affected by Sorafenib. Furthermore, Sorafenib diminished the activity of complex I in in-gel assays, whose expression and activity were restored by FeTPPs. However, Sorafenib did not affect the assembly of mitochondrial supercomplexes. Sorafenib altered glycolysis and reduced Krebs cycle intermediates and increased NAD/NADH ratio.</p><p><strong>Conclusions: </strong>The induction of cell death by Sorafenib was associated with peroxynitrite generation, which impacted the expression of ETC subunits and mitochondrial functionality in liver cancer cells.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"251-263"},"PeriodicalIF":7.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913557","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":"TNFAIP3 affects ferroptosis after traumatic brain injury by affecting the deubiquitination and ubiquitination pathways of the HMOX1 protein and ACSL3.","authors":"Lin Zhou, Lei Li, Jinghao Yang, Maierdan Mansuer, Xianyu Deng, Yida Wang, Hui Ren, Daming Cui, Yang Jiang, Liang Gao","doi":"10.1016/j.freeradbiomed.2024.12.048","DOIUrl":"10.1016/j.freeradbiomed.2024.12.048","url":null,"abstract":"<p><p>The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"221-239"},"PeriodicalIF":7.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913563","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}