The FASEB Journal最新文献

{"title":"Targeting Inflammation and Fibrosis in Cardiovascular Disease: Emerging Mechanisms and Therapies","authors":"Hector A. Cabrera-Fuentes,&nbsp;Guillermo Barreto,&nbsp;Eduardo Perez-Campos,&nbsp;Gilka F. Nivon-Torres,&nbsp;Aldo Abel Garcia González,&nbsp;Ebtesam Abdullah Al-Suhaim,&nbsp;Elisa A. Liehn","doi":"10.1096/fj.202500970R","DOIUrl":"10.1096/fj.202500970R","url":null,"abstract":"<div>\u0000 \u0000 <p>Cardiovascular diseases are increasingly recognized as chronic disorders driven by a complex interplay between inflammation and fibrosis. In this review, we elucidate emerging mechanisms that govern the transition from acute inflammation to pathological fibrosis, with particular focus on cellular crosstalk between neutrophils, macrophages, fibroblasts, and myofibroblasts. We explore how dysregulated immune responses and extracellular matrix (ECM) remodeling sustain a pathogenic feedback loop, promoting myocardial stiffening and adverse cardiac remodeling. Special attention is given to the plasticity of immune and stromal cells, including macrophage polarization and fibroblast-to-myofibroblast transitions, as well as the roles of TGF-β signaling, hypoxia, and noncoding RNAs. Building on this mechanistic foundation, we highlight next-generation therapeutic strategies—ranging from immunometabolic and epigenetic reprogramming to gene editing, cell-based therapies, and nanomedicine—designed to interrupt the inflammation–fibrosis axis. By targeting these interconnected pathways, emerging therapies offer the potential to reverse maladaptive remodeling, restore cardiac function, and redefine the treatment landscape in cardiovascular disease.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500970R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXO3 Protects Lens Epithelial Cells From UVB-Induced Oxidative Stress via the AMPK/FOXO3 Signaling Pathway","authors":"Yang Sun,&nbsp;Yingying Hong,&nbsp;Li Ning,&nbsp;Binghe Xiao,&nbsp;Maierdanjiang Ainiwaer,&nbsp;Yongxiang Jiang,&nbsp;Yinghong Ji","doi":"10.1096/fj.202501265RR","DOIUrl":"10.1096/fj.202501265RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Age-related cataract (ARC) represents a major global cause of visual impairment, with ultraviolet B (UVB) radiation recognized as a primary contributor to oxidative damage in the lens. FOXO3, a key regulator of aging, apoptosis, and oxidative stress-induced cell death, was investigated for its role and regulatory mechanisms in UVB-induced oxidative stress using human lens epithelial cells (HLECs). A progressive decrease in FOXO3 protein expression was observed in the lens capsules across various stages of cataract progression, as well as in UVB-exposed animal models and UVB-treated HLECs. Functional assays demonstrated that FOXO3 overexpression protected HLECs against UVB-induced damage by increasing cell viability, reducing reactive oxygen species (ROS) generation, and suppressing apoptosis. Furthermore, we demonstrated that the AMPK/FOXO3 signaling pathway is involved in this protective mechanism, as AMPK inhibition restored FOXO3 expression and mitigated UVB-induced cellular damage. Additionally, lncRNA SNHG12 was identified as a potential candidate regulated by FOXO3. Overexpressing FOXO3 in HLECs resulted in reduced lncRNA SNHG12 expression, whereas FOXO3 knockdown elevated lncRNA SNHG12 levels. Further luciferase reporter assays validated their interaction, revealing FOXO3 as a negative regulator of SNHG12 expression. Moreover, the knockdown of SNHG12 significantly attenuated apoptosis and oxidative stress induced by UVB in HLECs. In conclusion, these findings suggest that FOXO3 alleviates UVB-induced oxidative stress in lens epithelial cells through the AMPK/FOXO3 pathway and regulation of SNHG12, providing a potential therapeutic target for ARC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012922","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":"Burn Injury Triggers Distinct Transcriptomic Profiles in Adipose Tissue of Adult and Aged Mice","authors":"Punit Bhattachan,&nbsp;Filip Vlavcheski,&nbsp;Stephanie Wojtowicz-Piotrowski,&nbsp;Marc G. Jeschke","doi":"10.1096/fj.202501420R","DOIUrl":"10.1096/fj.202501420R","url":null,"abstract":"<div>\u0000 \u0000 <p>Severe burns are a major global health concern, and are associated with long-term physical and psychological impairments, multi-organ dysfunction, and substantial morbidity and mortality. While burn injuries in adults trigger systemic immuno-metabolic alterations—characterized by white adipose tissue browning, elevated resting energy expenditure, widespread catabolism, and inflammation—these adaptive responses are considerably impaired in older adults, with molecular mechanisms behind these differences remaining largely unclear. As a key regulator of systemic metabolism, investigating the pathological role of adipose tissue (AT) postburn may reveal novel targets that could potentially improve patient outcomes. In this study, we conducted bulk mRNA sequencing and analysis of AT from adult and aged mice to elucidate the transcriptomic changes underlying the distinct postburn responses in these populations. After examining differentially expressed genes in the adult and aged burn mice, the top six upregulated genes in adults (<i>Ucp1</i>, <i>Lgr6</i>, <i>Dio2</i>, <i>Lncbate10</i>, <i>Fabp3</i>, <i>Kng2</i>) were primarily associated with thermogenesis, whereas those in the aged mice (<i>Car6</i>, <i>Spata25</i>, <i>Gm128</i>, <i>Btbd16</i>, <i>Lipm</i>, <i>Abca13</i>) were linked to inflammation, tissue repair, and lipid metabolism. Furthermore, our gene co-expression and enrichment map analysis identified burn-associated modules related to fatty acid oxidation, acetyl thioester CoA, and thermogenesis in adults, whereas leukocyte migration, tumor necrosis factor production, and sister chromatids were in aged mice. Notably, <i>Ppara</i> and <i>Sfpi1</i> emerged as potential master regulators of co-expressed genes in burn AT of adult and aged mice, respectively. Our findings highlight age-specific differences in burn-induced AT responses and uncover potential molecular regulators that may inform targeted therapeutic strategies to mitigate the post-burn stress response.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012923","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":"Mitoribosome-Targeting Antibiotics Suppress Osteoclastogenesis and Periodontitis-Induced Bone Loss by Blocking Mitochondrial Protein Synthesis","authors":"Bulin Jiang,&nbsp;Yingyu Zeng,&nbsp;Han Zhu,&nbsp;Jimin Jiang,&nbsp;Fangyuan Cai,&nbsp;Hantao Yao,&nbsp;Chao Jiang,&nbsp;Fuming He","doi":"10.1096/fj.202501619R","DOIUrl":"10.1096/fj.202501619R","url":null,"abstract":"<div>\u0000 \u0000 <p>The onset and progression of periodontitis are closely related to metabolic reprogramming in the periodontal microenvironment, with osteoclasts playing a critical role in tissue destruction. Single-cell RNA sequencing (scRNA-seq) of periodontal tissues from healthy individuals and patients with severe chronic periodontitis revealed a significant increase in the expression of mitochondrial-related genes during osteoclast differentiation, suggesting the critical role of mitochondrial function in this process. This study investigates the potential of the novel mitoribosome-targeting antibiotic radezolid in inhibiting osteoclast differentiation. In vitro experiments showed that radezolid significantly suppressed osteoclast differentiation in RAW264.7 and bone marrow-derived macrophage (BMM) cells, and further analysis using flow cytometry and electron microscopy confirmed its inhibitory effect on mitochondrial function. Additionally, the addition of pyruvate was able to restore the NAD⁺/NADH ratio in the cells and partially reversed the inhibitory effects induced by radezolid. Finally, a rat model of periodontitis was used to validate the therapeutic potential of radezolid in inhibiting the progression of periodontitis. Taken together, these results suggest that radezolid, through targeting mitochondrial function, offers a novel therapeutic strategy for periodontitis treatment.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012921","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":"UTND Effect Mediates Macrophage Ferroptosis and Promotes Immune Microenvironment Remodeling of Ovarian Cancer","authors":"Changxin Shao,&nbsp;Shiqi Qiao,&nbsp;Yizi Meng,&nbsp;Tianxiao He,&nbsp;Lifeng Cui,&nbsp;Jin He","doi":"10.1096/fj.202500974R","DOIUrl":"10.1096/fj.202500974R","url":null,"abstract":"<div>\u0000 \u0000 <p>Tumor-associated macrophages (TAMs) act as a vital player in the immunosuppressive tumor microenvironment (TME) and have received widespread attention in the treatment of cancer in recent times. Nevertheless, simultaneously inducing TAM repolarization and strengthening their phagocytic ability on cancer cells is still a significant challenge. Ferroptosis has received widespread attention due to its lethal effects on tumor cells, but its role in TAMs and its impact on tumor progression have not yet been defined. Here, M2-type tumor-associated macrophages (M2-TAMs) targeted nanobubbles (NBs)-based (M2-pep@SF-NBs) were constructed for ultrasound-controlled delivery of the ferroptosis agonist sorafenib (SF) to enhance macrophage-mediated cancer immunotherapy. SF causes ferroptosis of M2 and regulates repolarization to M1 and promotes intratumoral (cytotoxic T lymphocyte) CTL infiltration, leading to activation of the TME that significantly inhibits tumor growth. Additionally, ultrasound (US)-induced macrophage ferroptosis notably improved the effectiveness of anti-PD-1 (aPD-1) therapy against tumors. M2-pep@SF-NBs were constructed to specifically target macrophage ferroptosis and repolarization, and combining this treatment with aPD-1 exerted significant anti-tumor efficacy. These findings lay the groundwork for deeper exploration of ferroptosis activation in TAMs and the regulation of their infiltration and function, aiming to enhance tumor prevention and therapeutic outcomes.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012917","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":"Red Blood Cell-Mediated Enhancement of Hematopoietic Stem Cell Functions via a Hes1-Dependent Pathway","authors":"Erika Yamashita,&nbsp;Soichiro Hashimoto,&nbsp;Hiroaki Abe,&nbsp;Takao Sudo,&nbsp;Daisuke Okuzaki,&nbsp;Toshiya Okawa,&nbsp;Masaru Ishii","doi":"10.1096/fj.202500885R","DOIUrl":"10.1096/fj.202500885R","url":null,"abstract":"<p>In bone marrow, cell numbers are balanced between production and loss. After chemotherapy, blood cell counts decrease initially but later recover as hematopoietic progenitor cells expand, although the mechanisms underlying this recovery are still unclear. We investigated the influence of red blood cells (RBCs) on hematopoietic stem cell (HSC) function during bone marrow recovery. Following chemotherapy, RBC concentrations in bone marrow peaked on day 5 posttreatment, coinciding with the recovery of hematopoiesis. Coculture of HSCs with RBCs resulted in a significant increase in hematopoiesis. Direct contact between RBCs and HSCs was essential for enhancement of hematopoiesis, and HSCs precultured with RBCs resulted in greater numbers of donor-derived mature hematopoietic cells after transplantation. RNA-sequencing analysis showed that Hes1 was the most significantly upregulated transcription factor in RBC coculture, and the response to RBC-induced hematopoiesis of Hes1-deficient HSCs was reduced. These findings imply a role of RBCs and Hes1 in the enhancement of hematopoietic recovery following bone marrow stress.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500885R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of FOXC1 Modified by METTL3/YTHDF1 Axis Aggravates NLRP3-Mediated Inflammasomes Formation and Cell Pyroptosis in Epilepsy","authors":"Pu Yang,&nbsp;Qian Yu","doi":"10.1096/fj.202500188R","DOIUrl":"10.1096/fj.202500188R","url":null,"abstract":"<div>\u0000 \u0000 <p>Epilepsy is a common chronic nervous system disease that threatens human health. However, the role of FOXC1 and its relations with pyroptosis have not been fully studied in epilepsy. Sprague–Dawley rats were obtained for constructing temporal lobe epilepsy (TLE) models. SH-SY5Y cells were treated with Mg²⁺-free medium for inducing in vitro cell models. H&amp;E, TIMM, and Nissl staining were employed for histological evaluation. Flow cytometry was used for measuring cell pyroptosis. ELISA was implemented for detecting the levels of inflammatory cytokines. Immunohistochemistry and immunofluorescence were performed to determine the expression and distribution of genes. ChIP, RIP, MeRIP, and dual-luciferase reporter analysis were performed to investigate the intermolecular interactions. The mRNA and protein level expression of genes were examined using RT-qPCR and western blotting. FOXC1 was lowly expressed in hippocampus tissue of TLE rats, and overexpression of FOXC1 alleviated neuronal damage. Overexpression of FOXC1 downregulated the levels of NLRP3, caspase 1, as well as IL-1β and IL-18 by inhibiting NLRP3-mediated pyroptosis in Mg²⁺-free–stimulated SH-SY5Y cells. Furthermore, FOXC1 bound to the promoter of NLRP3 and inhibited NLRP3 transcription. FOXC1 was found to be regulated by the METTL3/YTHDF1 axis-mediated m6A methylation. Overexpression of METTL3 attenuated Mg²⁺-free-induced neuronal injury and pyroptosis through YTHDF1-dependent regulation of FOXC1. Collectively, these data confirmed that FOXC1 suppressed neuronal injury and pyroptosis in epilepsy by transcriptionally inhibiting NLRP3, which might be correlated to METTL3/YTHDF1 axis-mediated m6A methylation.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012529","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":"External Cues as Transducers of Peripheral Tissue-Specific Molecular Clocks to Regulate Systemic Circadian Rhythms and Metabolism","authors":"Zhe Zhang,&nbsp;Bei-bei Liu,&nbsp;Shu-zhe Ding","doi":"10.1096/fj.202501289R","DOIUrl":"10.1096/fj.202501289R","url":null,"abstract":"<p>The molecular clock exhibits distinct characteristics across various tissues and can be synchronized by particular stimuli. Furthermore, there is an intricate interplay among the molecular clocks within different tissues. In this context, we present an overview of the tissue-specific molecular clock and discuss pivotal nonphotic regulators that govern the host's circadian rhythms and metabolic processes. Intermittent time-restricted feeding establishes rhythmicity and harmony in hepatic proteasome activity through various pathways and modulates hormone levels and lifespan extension via the synergistic action of molecular clocks and autophagy (AMPK, mTOR, SIRT1). High-fat diet (HFD) alters the molecular clock rhythms in the mediobasal hypothalamus (MBH), adipose tissue, and liver, with particularly pronounced changes observed in adipose tissue. HFD alters rhythm by inhibiting CLOCK:BMAL1 chromatin recruitment and activating the PPARγ pathway in the liver. The absence of liver CLOCK or intestinal BMAL1 mitigates metabolic disturbances, such as obesity, induced by long-term HFD. Meanwhile, intestinal microbiota also directly or indirectly regulates the host's circadian network and metabolism through micromolecules. Correspondingly, deletion of molecular clock genes alters the diurnal variations, composition, and function of the gut microbiome at the genus level in mice. The mechanisms underlying the tissue-specific effects of the gut microbiota on peripheral clocks are currently being unraveled and require further elucidation, with PPAR emerging as a pivotal factor in this process. The effect of exercise on the molecular clock of skeletal muscle varies depending on distinct muscle fiber types and the intensity of exercise. Identifying the optimal combination of chrono-exercise and intermittent fasting represents a substantial research opportunity. Additionally, the interplay between the molecular clocks of various tissues in response to specific rhythmic cues merits thorough investigation.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501289R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IRE1/XBP1s Axis Regulates Innate Immune Responses in Conventional Dendritic Cells During ZIKV Infection","authors":"Mónica Guzmán-Rodríguez,&nbsp;Tomás Hernández-Díaz,&nbsp;Paula Lisboa,&nbsp;Javier López-Schettini,&nbsp;Sofia Sanhueza,&nbsp;Lisette Leyton,&nbsp;Takao Iwawaki,&nbsp;Ricardo Soto-Rifo,&nbsp;Fabiola Osorio","doi":"10.1096/fj.202501186R","DOIUrl":"10.1096/fj.202501186R","url":null,"abstract":"<div>\u0000 \u0000 <p>Zika virus (ZIKV) is a mosquito-borne flavivirus causing a major epidemic in the Americas in 2015. Dendritic cells (DCs) are leukocytes with key antiviral functions, but their role in ZIKV infection remains under investigation. While most studies have focused on the monocyte-derived subtype of DCs, less is known about conventional dendritic cells (cDCs), essential for the orchestration of antiviral adaptive immunity. This study investigates the mechanisms by which cDCs respond to ZIKV for antiviral cytokine production. Here, using murine cultures, we demonstrate that ZIKV infection and not detection of ZIKV-infected dead cells activates cDCs by inducing type I interferons (IFN-I) and proinflammatory cytokines. Furthermore, ZIKV-infected cDCs markedly activated the IRE1/XBP1s axis of the unfolded protein response (UPR). Flow cytometry analysis indicates that among cDCs, type 1 cDCs (cDC1s) are responsible for ZIKV detection. Functionally, genetic loss of XBP1s curtailed expression of the costimulatory molecule CD86 and the production of IFN-I and proinflammatory cytokines by cDCs, without exhibiting increased susceptibility to ZIKV infection. These effects are attributable to perturbations in the IRE1/XBP1s axis and not due to overcompensation of PERK or IRE1 kinase signaling. Finally, tissue resident cDCs also exhibit susceptibility to infection, potentially establishing these cells as ZIKV targets in vivo. These findings underscore a critical role for the IRE1/XBP1s pathway in fine-tuning cDC activation to ZIKV, linking viral recognition to cDC functional maturation and opening new avenues for exploring UPR pathways targeting cDCs in the context of flavivirus infections.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012527","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":"Enriched Environment Alleviate AD Pathological Progression by Reducing Microglia Complement Signaling in Aged Male APP/PS1 Mice","authors":"Hai-Chao Chen,&nbsp;Jia-Xin Cao,&nbsp;Yi-Shu Zhang,&nbsp;Xiao-Mei Su,&nbsp;Yi-Ting Kang,&nbsp;Li-Ping Gao,&nbsp;Yu-Hong Jing","doi":"10.1096/fj.202501545RR","DOIUrl":"10.1096/fj.202501545RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is influenced by genetic and environmental factors. Previous studies showed that enriched environments improved memory and reduced amyloid plaques in AD mice, but the underlying mechanisms remain unclear. This study investigated the effects and mechanisms of enriched environments on AD pathology and cognitive function in aged APP/PS1 mice. Male APP/PS1 mice (15 months old) and wild-type littermates were divided into four groups: WT/SE, WT/EE, Tg/SE, and Tg/EE. Mice in EE groups were subjected to intervention with enriched environment for a period of 5 months. Results showed that enriched environments preserved cognitive function, reduced Aβ and p-Tau aggregation, and mitigated microglial inflammation (Tlr-4, NF-κB, iNOS). They also decreased C1q expression and slowed dendritic spine loss in hippocampal granule cells of APP/PS1 mice. These findings suggest that enriched environments can slow AD progression by regulating microglial inflammation and maintaining neuronal integrity, particularly in hippocampal dendritic spines.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998674","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}