ACS Chemical Neuroscience最新文献

{"title":"Pathogenic TRIM74 Mutation Disrupts Protein Homeostasis and Triggers Proteotoxic Neurodegeneration via Structural Destabilization.","authors":"S Rehan Ahmad, Abdullah M AlShahrani, Anupriya Kumari","doi":"10.1021/acschemneuro.5c00458","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00458","url":null,"abstract":"<p><p>Ubiquitin ligases play a critical role in maintaining proteostasis, synaptic function, and neuronal survival, and their dysfunction is increasingly implicated in neurodevelopmental disorders with neurodegenerative features. In this study, we investigate mutation in the ubiquitin ligase gene <i>TRIM74</i> [a novel homozygous missense variant c.562C > T (p.Pro121Leu)] in a 5-year-old male proband presenting with global developmental delay, hypotonia, seizures, and diffuse cerebral atrophy with mega cisterna magna. Structural and simulation studies revealed that Pro121, located at the start of a β sheet, likely functions as a sheet breaker. Substitution to leucine (P121L) resulted in aberrant beta strand extension, protein destabilization, and increased aggregation propensity. Free energy calculations indicated that all possible substitutions at this position were destabilizing. Multiple in silico prediction tools consistently classified the mutation as damaging or disease-causing. In proband-derived fibroblasts, TRIM74-P121L exhibited significant cytosolic aggregation and elevated Proteostat-positive granules, reflecting proteotoxic stress. Despite comparable transcript and total protein levels, mutant cells showed increased cell death and impaired cell cycle progression. Interaction network and gene ontology analyses revealed that TRIM74 and its partners are involved in ubiquitination, protein quality control, and transcriptional regulation─processes essential to neuronal homeostasis. TRIM74 expression was highest in the cerebellum and medulla, aligning with MRI abnormalities. Together, our findings establish the aberrant functioning of mutant TRIM74 as a pathogenic cause of neurodegenerative neurodevelopmental disorder and highlight the importance of ubiquitin ligases in maintaining neuronal integrity and preventing neurodegeneration.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Esketamine's Therapeutic Role for Perinatal Depression via TASK-1 Tandem Pore Potassium Channels.","authors":"Lin Zhu, Ji Chen, Yuan Liu, Wen Chen, Xinxin Liu, Fengrui Yang","doi":"10.1021/acschemneuro.5c00535","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00535","url":null,"abstract":"<p><p>This research focuses on the promising use of esketamine in perinatal depression, a widespread disorder impacting postpartum women's mental health. Despite esketamine's known rapid antidepressant effects, its precise mechanisms are not fully understood. This study integrates clinical and preclinical approaches to explore esketamine's efficacy in treating perinatal depression and its actions associated with TASK-1 potassium channels. A total of298 full-term pregnant women participated in a clinical trial, revealing that esketamine significantly lowers depression scores compared to controls. Alongside, mouse models were used to assess behavioral changes post-treatment, with findings highlighting reduced neuroinflammation and depressive-like symptoms, attributable to modulation via TASK-1 channels. Advanced gene expression analyses and cultured neuronal cell studies corroborated these findings, particularly through the modulation of synaptic plasticity proteins. Thus, esketamine offers a compelling therapeutic avenue for perinatal depression, with its effectiveness linked to specific neural pathways, encouraging further research and potential therapeutic developments.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Novel Triazole-Pyrazole Conjugates as Potential Anticonvulsant Agents: Synthesis and Biological Evaluations.","authors":"Wagdy M Eldehna, Mahmoud Abdelrahman Alkabbani, Zainab M Elsayed, Kawther Magdy Ibrahim, Taghreed A Majrashi, Mohamed Elagawany, Rofaida Salem, Hatem A Abdel-Aziz, Haytham O Tawfik","doi":"10.1021/acschemneuro.5c00392","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00392","url":null,"abstract":"<p><p>Since epilepsy is still a complex neurological condition, better and more efficient treatment methods are needed. This study used PTZ- and PIL-induced seizure models to evaluate the anticonvulsant activity of some recently synthesized compounds (<b>7a</b>-<b>f</b> and <b>11a</b>-<b>c</b>). Several candidates with significant seizure protection were found via initial screening in the PTZ model. In the pilocarpine model, compounds <b>7a</b> and <b>11a</b> showed the most promising efficacy by considerably delaying the start of seizures, lowering their severity, and increasing survival. According to biochemical analysis, both compounds successfully reduced oxidative stress, neuroinflammation, glial activation, and hippocampal excitotoxicity. Notably, <b>11a</b> matched or surpassed valproic acid's effects, especially in lowering astrocytic activation (GFAP), while <b>7a</b> performed better across all assessed parameters. The toxicological assessments validated both compounds' safety, and no evidence of neurotoxic, hepatic, renal, or cardiac damage was found. These results indicate the potential for additional preclinical development of <b>7a</b> and <b>11a</b> in epilepsy therapy by highlighting them as strong, safe, and versatile anticonvulsants.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced Positron Emission Tomography Imaging of β-Amyloid through Focused Ultrasound-Mediated Gallium-68 Radiotracer Delivery across the Blood-Brain Barrier.","authors":"Wenjing Li, Xiaochuan Zha, Xiaoyu Zhang, Haixin Dai, Suyun Pu, Xinya Yao, Wenxue Hui, Rui Xu, Junyu Bao, Jiahao Yu, Yan Wei, Jiawen Huang, Na Guo, Ming Xu, Jian Zhao, Bingbing Cheng, Zonghua Luo","doi":"10.1021/acschemneuro.5c00476","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00476","url":null,"abstract":"<p><p>Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is an innovative approach for enhancing the delivery of central nervous system drugs. ⁶⁸Ga radiotracers are advantageous for imaging due to their ideal half-life and imaging properties; however, their limited ability to traverse the BBB constrains their application in brain imaging. This study investigates the application of FUS to selectively deliver the ⁶⁸Ga radiotracer, [⁶⁸Ga]STZL4110, into the hippocampus for β-amyloid positron emission tomography (PET) imaging in an Alzheimer's disease (AD) mouse model. The synthesis and radiolabeling of [⁶⁸Ga]STZL4110 were accomplished, demonstrating robust binding to β-amyloid, as validated by Thioflavin T assays and <i>in vitro</i> autoradiography with both wild-type (WT) and APP/PS1 AD mouse brain sections. Cavitation activity measurements confirmed effective and consistent BBB opening post-FUS treatment, ensuring targeted delivery without vascular damage, as supported by histological analysis. Quantitative PET imaging revealed the successful detection of β-amyloid deposition following FUS treatment. Initially, [⁶⁸Ga]STZL4110 showed a low volume of distribution in the right hippocampus of AD mice. FUS application significantly enhanced BBB permeability, leading to a 74% increase in [⁶⁸Ga]STZL4110 uptake in the targeted right hippocampus of APP/PS1 mice compared with the left hippocampus, whereas no significant change was observed in WT mice. These findings suggest that combining FUS with [⁶⁸Ga]STZL4110 could significantly enhance the sensitivity and specificity of ⁶⁸Ga PET imaging for β-amyloid. FUS-mediated PET imaging may potentially address the challenge of effective brain imaging with radiotracers that traditionally exhibit a low penetration of the BBB.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the Relationship between Alzheimer's Disease and Type-2 Diabetes via the Protein Aggregation Prism.","authors":"Vaishnavi Tammara, Atanu Das","doi":"10.1021/acschemneuro.5c00357","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00357","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and type-2 diabetes (T2D) are two fatal human diseases and have been linked to the aberrant aggregation of two distinct peptides, amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. These two peptide aggregates, even with distal deposition sites (brain and pancreas), act as mutual beneficiaries. We here unveiled the crosstalk in a self-consistent fashion using atomistic simulations by comparing the kinetics and thermodynamics of self- and cross-aggregations of Aβ₄₂ and hIAPP and their modulations by preformed fibrillar templates. Templates (specifically hIAPP) generally accelerate aggregation, alter the relative order of aggregation rates (cross-aggregation > Aβ self-aggregation > hIAPP self-aggregation for nontemplated and hIAPP self-aggregation > cross-aggregation > Aβ self-aggregation for templated), and flip the mutual impact (hIAPP aggravates Aβ aggregation in nontemplated and the reverse in templated). Higher instances of breaking larger aggregates and longer residence times of smaller aggregates decelerate aggregation, whereas interpeptide electrostatics (universal) and hydrogen bonds (templated) assist it. However, the equilibrium aggregability pattern contradicts kinetic rank-ordering, as Aβ displays a higher aggregability than hIAPP, templates increase aggregability for both peptides, and Aβ's self-aggregability supersedes cross-aggregability, which further surpasses hIAPP's self-aggregability. The equilibrium ensembles encompass polymorphic, nonfibrillar oligomers having substantially reduced α-helicity and slight β-propensity, with both parallel and antiparallel interpeptide orientations, primarily stabilized by electrostatics. A higher equilibrium aggregability means a greater helix-breaking capacity, a bias toward parallel orientation, and a lesser structural polymorphism. Water expulsion from peptide surroundings and distortion of water tetrahedrality prove that aggregation follows the liquid-liquid phase separation (LLPS) model.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu²⁺-Aβ Aggregation and Reactive Oxygen Species.","authors":"Gagandeep Kaur, Opinder Kaur Mankoo, Amandeep Kaur, Sukhmani Mann, Nitesh Priyadarshi, Prit Pal Singh, Bhupesh Goyal, Nitin Kumar Singhal, Deepti Goyal","doi":"10.1021/acschemneuro.5c00386","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00386","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives <b>4</b>(<b>a</b>-<b>p</b>). In particular, <b>4k</b> with an <i>o</i>-I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency <b>4k</b> = 90.5%, IC₅₀ = 6.51 ± 0.01 μM) against Aβ₄₂ aggregation as compared to 38.1% noted for CQ. Furthermore, <b>4k</b> significantly disassembled the preformed Aβ₄₂ fibrils (Aβf, 92.5%), chelated Cu²⁺ ions, and inhibited Cu²⁺-mediated Aβ₄₂ aggregation. Compound <b>4k</b> ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound <b>4k</b> has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ₄₂ aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ₄₂ in the presence of <b>4k</b>, we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ₄₂ monomer (Aβm) and Aβf on the incorporation of <b>4k</b>. Compound <b>4k</b> modulates Aβ₄₂ fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of <b>4k</b> to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The <b>4k</b>-induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by <b>4k</b> illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Therapeutic Potential of Ar-tur in Alzheimer Disease: A Cheminformatics, Pharmacokinetics, and System Pharmacology Approach.","authors":"Reiya Bosco Don Bosco, Johnson Retnaraj Samuel Selvan Christyraj, Jenif Leo Anandharaj, Beryl Vedha Yesudhason","doi":"10.1021/acschemneuro.5c00147","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00147","url":null,"abstract":"<p><p>Acquisition and consolidation of recognition memory involves dopaminergic activity, which is determined to be dysregulated in Alzheimer disease (AD). Aromatic turmerone (Ar-tur), one of the major bioactive components of <i>Curcuma longa</i>, has been identified to protect dopaminergic neurons from various pathological insults. We have computationally investigated the drug-like nature and the therapeutic potential of Ar-tur in treating AD and have compared its targets with FDA-approved AD drugs. Cheminformatics, pharmacokinetics, toxicity, and system pharmacology studies were performed in predicting the drug-like properties, protein targets, toxicity profiles, target's functional association, and enrichment analysis of Ar-tur. Notably, Ar-tur had targeted 94 proteins, and 29 proteins of these proteins were among the top 15 targets of the 20 FDA-approved drugs. These targets were identified to be dysregulated in the hippocampus and entorhinal cortex in the AD brain, signifying that targets of Ar-tur play roles in disease modification and regulation. Based on gene ontology analysis, KEGG, Reactome, and WikiPathways, we identified that Ar-tur regulates dopamine neurotransmitter receptor activity and dopamine binding activity. Dopamine receptors (DRs), DR2 and DR4, were among its top 15 targets of Ar-tur. Molecular docking of DRs with dopamine, cariprazine, brexpiprazole, RO-10-5824, CP226269, and donepezil connotes that Ar-tur behaves like an agonist of DR2 and DR4 by binding to the active site residues like the dopamine and DR agonists. This is the first report stating the impressive drug-like properties of Ar-tur and holds the potential to rescue the vulnerable dopaminergic system by regulating DRs.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ULK1 Knockout Exacerbates Ischemia-Induced Microglial Dysfunction via TRAF6/NF-κB Signaling Pathway.","authors":"Ye Xiong, Zhuo Li Li, Xiao Wan Wang, Ting Li, Mai Yin Cui, Min Min Wang, Yan Qiong Fu, Yu Zheng, Wei Wei Xiang, Yang Wang, Bai Hui Chen","doi":"10.1021/acschemneuro.5c00284","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00284","url":null,"abstract":"<p><p>Activated microglia rapidly migrate to the infarct site, mediate neuroinflammation, and phagocytose cell debris during the acute stage of ischemic stroke; however, the underlying mechanisms remain unclear. In this study, we utilized a cortical photothrombotic ischemic model and found that unc-51-like autophagy activating kinase 1 (ULK1) knockout mice exhibited increased pro-inflammatory microglia, along with upregulated levels of pro-inflammatory mediators. Further studies revealed that ULK1 deletion impaired the phagocytosis of myelin debris by microglia, thereby exacerbating myelin accumulation in the infarct zone and increasing pro-inflammatory phagocytic microglia. Moreover, coimmunoprecipitation results showed that ULK1 bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) in primary microglia. Subsequently, we observed that the protein levels of ULK1 and phosphorylated nuclear factor κ-B (p-NF-κB) were regulated by the administration of the TRAF6 inhibitor C25-140 in ischemic wild-type (WT) mice. Overall, our study suggests that ULK1 regulates microglial activation and neuroinflammation via the TRAF6/NF-κB signaling pathway in ischemic stroke.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychedelics, Spirituality, and Fundamentalism: A Brain Network Approach to Cognitive Flexibility and Rigidity.","authors":"Anjian Yang, Xinyou Lv, Hongshuang Wang, Xiaohui Wang","doi":"10.1021/acschemneuro.5c00509","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00509","url":null,"abstract":"<p><p>This viewpoint reconceptualizes mysticism and fundamentalism as brain network disorders, with psychedelics like psilocybin, lysergic acid diethylamide, and N,N-dimethyltryptamine offering potential to modulate these states. By disrupting rigid neural patterns, psychedelics may foster cognitive flexibility, challenge inflexible belief systems, and offer therapeutic value for extremism and mental health disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown SIRT6 Alleviates Blood-Brain Barrier Disruption after Subarachnoid Hemorrhage through Inhibiting Ferroptosis by Promoting SMARCA2 Acetylation.","authors":"Li Lv, Long Zhang, Yan Wang, Haipeng Xi","doi":"10.1021/acschemneuro.5c00300","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00300","url":null,"abstract":"<p><p>Ferroptosis has been identified as a mechanism underlying subarachnoid hemorrhage (SAH), attributed to blood-brain barrier (BBB) disruption. This study aimed to explore whether SIRT6 mediates ferroptosis affecting BBB disruption after SAH and the potential mechanism. Knockdown SIRT6 improved the neural function score in SAH rats, reduced the escape latency, increased the number of entering the target quadrant and the time of staying in the platform quadrant, and inhibited apoptosis while reducing brain water content and BBB disruption, leading to an improvement in neurological deficits after SAH. Concomitantly, knockdown SIRT6 increased OxyHB-induced brain microvascular endothelial cells (BMECs) viability, inhibited apoptosis, preserved tight junction proteins (Claudin-3, Occludin, and ZO-1) levels, and decreased adhesion molecules (ICAM-1 and VCAM-1) levels, thereby mitigating endothelial barrier dysfunction. Additionally, knockdown SIRT6 inhibited the OxyHb-induced ferroptosis in BMECs. Furthermore, ferroptosis inhibitor ferrostatin 1 reversed the proferroptosis effects of SIRT6 overexpression. Mechanically, SIRT6 knockdown reduced ferroptosis and endothelial barrier dysfunction after SAH by promoting SMARCA2 acetylation. Our results suggested that knockdown SIRT6 inhibited ferroptosis by promoting SMARCA2 acetylation, thereby alleviating BBB disruption after SAH. These findings establish a novel SIRT6-SMARCA2 axis governing ferroptosis in SAH, providing mechanistic insights into BBB protection. Our findings may represent promising strategies for the clinical management of SAH.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}