The FASEB Journal最新文献

{"title":"Mitochondrial Calcium Uniporter-Mediated Regulation of the SIRT3/GSK3β/β-Catenin Signaling Pathway in Vascular Remodeling","authors":"Min Jiang,&nbsp;Lejian Lin,&nbsp;Shuai Yue,&nbsp;Shujin Shi,&nbsp;Haojie Yan,&nbsp;Hui Yi,&nbsp;Fan Han,&nbsp;Shuai Xu,&nbsp;Junjie Su,&nbsp;Ran Zhang","doi":"10.1096/fj.202500369RR","DOIUrl":"https://doi.org/10.1096/fj.202500369RR","url":null,"abstract":"<p>Calcium homeostasis plays a crucial role in regulating the phenotype of vascular smooth muscle cells (VSMCs) and vascular remodeling. This study aims to investigate the role of the mitochondrial calcium uniporter (MCU), which facilitates the uptake of Ca²⁺ into the mitochondria, in vascular remodeling and its underlying regulatory mechanisms. Vascular remodeling in rats was induced through either 21-day hindlimb unloading (HU) or 21-day angiotensin II (Ang II) infusion (0.7 mg/kg/day). Phenotypic switching of VSMCs and vascular remodeling were assessed. To induce phenotypic switching and clarify the underlying regulatory mechanisms, VSMCs were treated with Ang II (100 μmol/L). Gene manipulation was performed using plasmids, lentivirus, and adeno-associated virus serotype 9 (AAV9). Mitochondrial oxidative stress, Ca²⁺ distribution, and the expression of MCU, SIRT3, GSK3β, and β-catenin, along with GSK3β activity, SIRT3 ubiquitination, and GSK3β acetylation, were evaluated. The expression of MCU and SIRT3 in rat cerebral arteries was downregulated following HU and Ang II administration, which resulted in an increase in cytoplasmic Ca²⁺, a decrease in mitochondrial Ca²⁺, and a shift toward a synthetic phenotype in VSMCs. In vitro, Ang II treatment of VSMCs led to reduced expression of MCU, SIRT3, and GSK3β, and increased nuclear translocation of β-catenin. Knockdown of MCU caused an increase in cytoplasmic Ca²⁺ and a reduction in mitochondrial Ca²⁺, while MCU overexpression had the opposite effect, decreasing cytoplasmic Ca²⁺ and increasing mitochondrial Ca²⁺. Additionally, MCU overexpression decreased SIRT3 ubiquitination, mitochondrial oxidative stress, GSK3β acetylation, nuclear translocation of β-catenin, and VSMC phenotypic switching—these effects were blocked by SIRT3 knockdown. Moreover, MCU overexpression partially mitigated vascular remodeling in HU and hypertensive rats by inhibiting the GSK3β/β-catenin pathway and preserving SIRT3. Ang II regulates MCU protein expression, which is reduced in the HU and Ang II-induced hypertensive rat cerebral arteries. This reduction impairs cellular Ca²⁺ buffering and promotes mitochondrial oxidative stress. The stress response triggers the downstream degradation of SIRT3, which subsequently inhibits the activity of GSK3β via acetylation and promotes the nuclear translocation of β-catenin, thereby facilitating phenotypic switching and vascular remodeling.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500369RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573377","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":"MiR-30d-5p Regulates Bone Remodeling and Vessel Remodeling in Osteoporosis by Targeting GRP78","authors":"Jie Li,&nbsp;Ran Kang,&nbsp;Guang Li,&nbsp;Xinle Li,&nbsp;Daquan Liu,&nbsp;Lidong Zhai,&nbsp;Jianxiong Ma,&nbsp;Lei Yang,&nbsp;Ping Zhang","doi":"10.1096/fj.202500345R","DOIUrl":"https://doi.org/10.1096/fj.202500345R","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoporosis is one of the major bone disorders that has a close relationship with osteogenesis and angiogenesis. MiRNA coordinates a cascade of anabolic and catabolic processes in bone homeostasis and dynamic vascularization. Here, the role of miR-30d-5p in osteoporosis and its mechanism were investigated. To explore the effect of miR-30d-5p on osteogenesis and angiogenesis, an ovariectomized (OVX) mouse model, bioinformatics analysis, and multiple in vitro assays were used. Compared to the sham group, OVX mice reduced BV/TV, Tb.Th, Tb.N, and BMD, while it increased Tb.Sp. The number of osteoblasts and the density of microvessels were decreased in the OVX group, while the number of osteoclasts was increased. MiRNA sequencing and qRT-PCR revealed that miR-30d-5p was increased in the bone marrow cells of the OVX mice. Supplementing miR-30d-5p activity using miR-30d-5p agomir inhibited osteogenic differentiation in bone marrow-derived cells and prevented angiogenesis in HUVECs. Conversely, miR-30d-5p antagomir, an inhibitor of endogenous miR-30d-5p, reversed the inhibitory responses. Glucose regulating protein 78 (GRP78), a key regulator of endoplasmic reticulum stress, was demonstrated to be directly targeted by miR-30d-5p. Consistently, the overexpression of GRP78 improved miR-30d-5p-related osteoblast differentiation and angiogenesis. We concluded that miR-30d-5p significantly inhibited bone formation and blood vessel formation by targeting GRP78 in experiments in vitro. Therefore, miR-30d-5p may serve as a potential target for reversing osteoporosis.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558197","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":"Exosomal Gene Biomarkers in Osteosarcoma: Mifepristone as a Targeted Therapeutic Revealed by Multi-Omics Analysis","authors":"Zheng Li,&nbsp;Jie Guo,&nbsp;Shaopeng Zhu,&nbsp;Yunpeng Zou,&nbsp;Wenqi Ma,&nbsp;Jiayao Niu,&nbsp;Ronghan Liu,&nbsp;Kai Zhao","doi":"10.1096/fj.202501151RR","DOIUrl":"https://doi.org/10.1096/fj.202501151RR","url":null,"abstract":"<p>Osteosarcoma (OS) is an aggressive bone cancer that mainly occurs in children and adolescents. OS patients are mainly treated with neoadjuvant chemotherapy and surgical resection. This treatment is effective for early osteosarcoma. However, the effect declines as the disease progresses. Currently, our research on osteosarcoma is not enough to meet the clinical needs. Exosomes play a critical role in osteosarcoma progression by mediating intercellular communication. They carry molecular signals, including miRNAs and proteins, which can influence tumor growth, metastasis, and drug resistance. Recent studies have shown that exosomes from osteosarcoma cells can promote cell proliferation and migration, making them potential biomarkers for early diagnosis and therapeutic targets in osteosarcoma. This opens up new possibilities for the research of osteosarcoma. The combined genes of exosomes and DEGs were identified by searching GeneCards and GEO databases. Subsequent analyses included GO and KEGG Enrichment, GSEA. The core gene set was derived from the intersection of LASSO and SVM-RFE outputs, ensuring minimal redundancy through dimensionality reduction. Osteosarcoma was diagnosed and predicted by differential expression levels, ROC curve analysis, and nomogram. Immune cell infiltration in osteosarcoma was evaluated by the ssGSEA algorithm. Drug enrichment analysis and molecular docking simulations were conducted to discover the most promising drug leads. In vitro experiments included Wound Healing Assay and qRT-PCR to detect the therapeutic effect of the drug. Through multiple analyses and dimensionality reduction of the data set, six genes were selected (WNT5A, GCA, ANXA6, BIRC5, IL1β, and ARPC3). We examined differential expression in the control and tumor groups and made a gene prediction nomogram. Analysis of immune cell infiltration revealed significant alterations in the composition of immune cell subsets. Drug enrichment analysis and molecular docking of these six core genes were conducted to screen out the most suitable candidate drug: Mifepristone. Finally, Mifepristone was proved to inhibit the growth of osteosarcoma cells in vitro. Bioinformatics analysis identified six exosome-associated osteosarcoma genes (WNT5A, GCA, ANXA6, BIRC5, IL1β, and ARPC3) that could serve as potential biomarkers. Through screening, Mifepristone, which can act on BIRC5 and IL1β at the same time, has a very effective osteosarcoma treatment effect.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501151RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558161","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":"AlkB Homolog 5 Regulates Hexokinase 2-Mediated Glycolysis and Participates in the Progression of Endometriosis","authors":"Jun-Jun Liu,&nbsp;Yu-Qing Fang,&nbsp;Wen-Qian Xiong,&nbsp;Heng-Wei Liu,&nbsp;Jing-Yi Li,&nbsp;Xiu-Ping Wang,&nbsp;Hua-Jing Wang,&nbsp;Ling Zhang,&nbsp;Yi Liu","doi":"10.1096/fj.202500614R","DOIUrl":"https://doi.org/10.1096/fj.202500614R","url":null,"abstract":"<div>\u0000 \u0000 <p>Endometriosis is a common gynecological endocrine disease with unclear pathogenesis. Evidence suggests enhanced aerobic glycolysis in ectopic endometrium of endometriosis. The role of N6-methyladenosine (m6A) modification in female reproductive diseases has been revealed in recent years, and it is involved in the regulation of glycolysis in a variety of diseases. Here, we investigated the regulatory effect of m6A modification on glycolysis and its role in endometriosis. RNA sequencing of ectopic endometrium of endometriosis and normal endometrium revealed that hexokinase 2 (HK2) a glycolysis-related gene, was significantly up-regulated in ectopic endometrium of endometriosis. Meanwhile, this result was supported by immunohistochemistry. Subsequently, we found that AlkB homolog 5 (ALKBH5) could upregulate HK2 in human endometrial stromal cells (THESCs). Up-regulation of ALKBH5 promoted glycolysis, invasion, and migration of THESCs, which could be alleviated by 2-Deoxy-d-glucose (2-DG). Furthermore, knockdown of HK2 in THESCs overexpressing ALKBH5 significantly attenuated the promoting effects of ALKBH5 on glycolysis, migration, and invasion of THESCs. Moreover, an ALKBH5 inhibitor, 5-Carboxy-8-hydroxyquinoline (IOX1) was found to inhibit the progression of endometriosis and glycolysis in a mouse model of endometriosis. In conclusion, ALKBH5 promoted glycolysis by up-regulating HK2 and contributed to the progression of endometriosis. ALKBH5 may be a new target for the treatment of endometriosis.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558196","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":"Small Molecules as Regulators of Liquid–Liquid Phase Separation: Mechanisms and Strategies for New Drug Discovery","authors":"Abdurrahman Usman,&nbsp;Anas Yusuf,&nbsp;Murtala Bindawa Isah,&nbsp;Mei Dang,&nbsp;Xiaoying Zhang","doi":"10.1096/fj.202501476R","DOIUrl":"https://doi.org/10.1096/fj.202501476R","url":null,"abstract":"<div>\u0000 \u0000 <p>Condensate-modifying therapeutics (c-mods), comprising low–molecular-weight compounds (~1.5 kDa) and related agents such as RNAs and metabolites like ATP, are emerging as promising drug candidates for neurodegenerative disorders, cancer, and viral infections. These compounds modulate liquid–liquid phase separation (LLPS), a biophysical process driven by intrinsically disordered regions, low-complexity domains, and multivalent non-covalent interactions (hydrogen bonds, van der Waals forces, hydrophobic, and electrostatic interactions). LLPS governs the formation of biomolecular condensates essential for gene regulation, signaling, stress responses, and cellular organization. By selectively inhibiting or promoting condensation, we show that c-mods offer strategies to manage diseases presented with aberrant phase separation. Mechanistic insights into LLPS dynamics provided by specific physicochemical features (planar structures and polarity) of c-mods open avenues for accelerating drug discovery, repurposing, and synergistic therapies. We highlight scaffolds, charged molecules, and ions that modulate LLPS. We integrate recent advances in understanding the roles of c-mods in regulating viral protein assemblies; however, the function of LLPS and its regulation in other microorganisms remains underexplored. Future directions include engineering peptide-based therapeutics, designing artificial condensates, and employing AI-driven target identification to discover novel LLPS-associated drug targets. Additionally, biomaterials and industry-led initiatives in condensate-targeted drug discovery are broadening therapeutic intervention across diverse diseases.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501476R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558181","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":"Resistance and Aerobic Preconditioning Delays Unloading-Induced Multisystemic Physiological Changes: The NEBULA Project","authors":"Théo Fovet,&nbsp;Margot Issertine,&nbsp;Pauline Jacob,&nbsp;Stephanie Ghislin,&nbsp;Norbert Laroche,&nbsp;Sandrine Roffino,&nbsp;Claire Camy,&nbsp;Julian Theuil,&nbsp;Christelle Bertrand-Gaday,&nbsp;Pierre Delobel,&nbsp;Béatrice Chabi,&nbsp;Vincent Ollendorff,&nbsp;Guillaume Py,&nbsp;Jean-Pol Frippiat,&nbsp;Jean-Luc Morel,&nbsp;Laurence Vico,&nbsp;Thomas Brioche,&nbsp;Maura Strigini,&nbsp;Angèle Chopard","doi":"10.1096/fj.202501128R","DOIUrl":"https://doi.org/10.1096/fj.202501128R","url":null,"abstract":"<p>Spaceflight is considered an extreme environment, and from the first days of flight, microgravity causes significant modifications in several physiological systems, particularly the musculoskeletal, cardiovascular, immunological, and nervous systems. To safeguard astronauts' health on upcoming trips, it is crucial to better counteract microgravity's effects using the best prevention methods. With this objective, we launched the NEBULA (Nutrition and Exercise Biology for UnLoaded Astronauts) collaborative research project. The first phase of NEBULA investigates whether a targeted high-intensity pre-flight training program (preconditioning) can delay physiological deconditioning during the initial days of microgravity in a preclinical model. To assess this, sixty 16-week-old male C57BL/6J mice were split into 6 groups (<i>n</i> = 10, each). Half underwent three weeks of preconditioning training (PreC), while the other half remained untrained (Ctrl). Both groups then experienced either 7 or 21 days of hindlimb unloading (HU). Tissue samples—including muscle, bone, tendon, bone marrow, spleen, serum, and brain—were collected at three key time points: post-preconditioning (HU0), after 7 days of HU (HU7), and after 21 days of HU (HU21). At HU0, the PreC group exhibited significantly improved physical performance and enhanced musculoskeletal mass and architecture compared to Ctrl. In the Ctrl group, HU induced severe bone and muscle deconditioning by HU7, which was worsened by HU21. However, in the PreC group, the initial improvements in bone and muscle structure were maintained through HU7 before declining by HU21. Importantly, the high intensity and frequency of training did not negatively impact tendon integrity or immune function and appeared to prevent the decline in adult neurogenesis typically associated with both intense exercise and microgravity. These findings highlight the broad systemic benefits of pre-flight physical conditioning in delaying the adverse effects of reduced mechanical load, such as those experienced during spaceflight or prolonged bed rest. Additionally, they underscore the potential for preconditioning to support more effective countermeasures when physical exercise is unavailable for extended periods.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501128R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558215","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":"Dynamic Leader–Follower Hierarchies in Collective Cell Migration","authors":"Yuan Wan,&nbsp;Huifen Liu,&nbsp;Kun Mi","doi":"10.1096/fj.202501065R","DOIUrl":"https://doi.org/10.1096/fj.202501065R","url":null,"abstract":"<div>\u0000 \u0000 <p>Collective migration of cancer cells, characterized by a structured leader–follower hierarchy, has emerged as a critical mechanism driving metastasis. During this process, leader cells play a pivotal role in environmental sensing, pathfinding, and signal transduction, while follower cells actively respond to these signals, facilitating stress transmission through cytoskeletal dynamics and cell–cell adhesions. Together, these interactions promote coordinated cancer invasion and metastasis. This review synthesizes current knowledge on the molecular mechanisms underlying leader–follower dynamics, with a particular emphasis on the role switching between them and the interplay of key signaling pathways. Building on recent studies, we explore how leader–follower plasticity influences collective behaviors and discuss its implications for cancer progression. By elucidating these mechanisms, we aim to identify potential therapeutic targets and propose novel strategies for disrupting collective invasion, offering new perspectives for cancer treatment.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501065R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558223","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":"Research Progress on the Regulation of Macrophages for Cardiovascular Diseases","authors":"Ke Wu,&nbsp;Hong-Xia Ma,&nbsp;Zhong-Yan Li,&nbsp;Yan Li,&nbsp;Di Wu,&nbsp;Hui-Yi Lu","doi":"10.1096/fj.202501352R","DOIUrl":"https://doi.org/10.1096/fj.202501352R","url":null,"abstract":"<div>\u0000 \u0000 <p>With the rising incidence of cardiovascular disease (CVD), an array of preventive and therapeutic strategies is under investigation. The intersection of immunity and inflammation in CVD is a particularly active research domain. Within this context, macrophages—key players in innate immunity—have emerged as potential targets for CVD treatment and prevention. Generally, macrophages confer cardioprotection by balancing M1/M2-type polarization and modulating cardiomyocyte activity through the recognition of danger signals via surface receptors. This process is critical for maintaining intracellular homeostasis and regulating immune responses. This review further elucidates the significant role of macrophages in the pathophysiological processes of inflammation, lipid oxidation, cardiac dysfunction, and myocardial electrical remodeling associated with CVD, highlighting conditions such as atherosclerosis, myocardial infarction, myocardial fibrosis, arrhythmias, and hypertension. The overarching goal of this review is to offer a comprehensive overview of macrophage polarization and surface receptors/molecules in CVD, thereby fostering the identification of novel targets and innovative approaches for CVD treatment.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501352R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558224","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":"MS275 Inhibits Neuroblastoma Cell Growth by Mediating H3K27ac/PROX1 Axis In Silico and In Vitro","authors":"Chao Yuan,&nbsp;Chaoqun Li,&nbsp;Junwei Lu,&nbsp;Shengjie Liao,&nbsp;Runkun Wu,&nbsp;Duanzhuo Li,&nbsp;Mi Huang,&nbsp;Dacong Gong,&nbsp;Weibin Wu,&nbsp;Xin Yu,&nbsp;Shinuan Fei,&nbsp;Wenxia Si","doi":"10.1096/fj.202500464RR","DOIUrl":"https://doi.org/10.1096/fj.202500464RR","url":null,"abstract":"<p>Neuroblastoma, a prevalent pediatric solid tumor, is characterized by substantial genetic, morphological, and clinical heterogeneity, which poses challenges to the efficacy of existing therapeutic interventions. Previous studies have demonstrated that the histone deacetylase (HDAC) inhibitor MS275 can impede the growth of neuroblastoma cells. However, the precise mechanisms underlying this inhibitory effect remain inadequately understood. To assess the impact of MS275 on neuroblastoma cell proliferation, a series of assays, including CCK8, colony formation assay, EdU assay, cell cycle assay, and apoptosis assays, were conducted. Furthermore, the qRT-PCR, western blotting, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assays were utilized to elucidate the regulatory relationship between MS275 and PROX1 expression. To further ascertain the role of PROX1 in MS275-mediated tumor suppression, in silico analyses were complemented by the establishment of PROX1 knockdown SH-SY5Y cell lines and xenograft models. The cell functional assays revealed that MS275 exerts an inhibitory effect on neuroblastoma cell proliferation by inducing G1/S cell cycle arrest, apoptosis, and autophagy in a dose-dependent manner. Notably, the reduction of PROX1 expression was observed to partially reverse the inhibitory effects of MS275 on neuroblastoma cells, affecting cell cycle progression, apoptosis, autophagy-related factors, and tumor growth. Mechanistically, MS275 was found to significantly enhance and modify the transcription of PROX1 through the induction of H3K27 acetylation. In summary, these findings highlight the crucial role of PROX1 in MS275-mediated tumor suppression and unveil a novel regulatory mechanism involving PROX1, suggesting its potential as a promising therapeutic target for neuroblastoma.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500464RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537105","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 Regulatory Mechanisms of Treponema pallidum Enolase on Macrophages: From Enzymatic Activity to Signal Transduction","authors":"Peiyuan Sun,&nbsp;Suo Liu,&nbsp;Qilin Zeng,&nbsp;Weiwei Li,&nbsp;Sijia Li,&nbsp;Zhanpeng Wang,&nbsp;Yuanyuan Tang,&nbsp;Hongyu Yang,&nbsp;Dongde Xie,&nbsp;Jun Zhou,&nbsp;Yanxia Zhou,&nbsp;Kang Zheng,&nbsp;Yimou Wu","doi":"10.1096/fj.202500358R","DOIUrl":"https://doi.org/10.1096/fj.202500358R","url":null,"abstract":"<p>Syphilis, caused by the gram-negative bacterium <i>Treponema pallidum</i>, remains a significant global public health threat. Despite the efficacy of antibiotic treatment in controlling syphilis, the pathogenic mechanisms of <i>T. pallidum</i>, particularly its interactions with the host immune system, are not well understood. This study aimed to investigate the potential immunomodulatory role of <i>T. pallidum</i> enolase (Eno) in promoting macrophage apoptosis through the P2X7R and reactive oxygen species (ROS)/NF-κB pathways, offering new insights into the pathogen's immune evasion strategies. Bioinformatics analysis identified <i>T. pallidum</i> Eno as a hydrophilic cytoplasmic protein that plays a crucial role in glycolysis. In vitro experiments demonstrated that <i>T. pallidum</i> Eno can be successfully expressed and purified in <i>Escherichia coli</i>, resulting in significant induction of macrophage apoptosis. Mechanistic studies revealed that <i>T. pallidum</i> Eno activates caspase family members, decreases mitochondrial membrane potential, and triggers the apoptotic program in macrophages. Additionally, we found that <i>T. pallidum</i> Eno stimulates the production of ROS, subsequently activating the NF-κB signaling pathway and promoting the transcription of apoptosis-related genes. This study further highlights the role of <i>T. pallidum</i> Eno in modulating host immune responses by inducing the secretion of interleukin-8, interleukin-6, and interleukin-1β, which are involved in macrophage chemotaxis and activation. Collectively, these findings suggest that <i>T. pallidum</i> may exploit the host inflammatory response to enhance its dissemination and evade immune clearance. The multifaceted functions of <i>T. pallidum</i> Eno in cell metabolism and immune regulation provide new insights into the pathogenesis of syphilis and offer potential targets for therapeutic intervention.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500358R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537106","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}