The FASEB Journal最新文献

{"title":"Capicua Refines Mossy Fiber–CA3 Axon Targeting in the Late Postnatal Hippocampus","authors":"Rebekah van Bruggen,&nbsp;Karla Manzanet Freyre,&nbsp;Mi Wang,&nbsp;Qiumin Tan","doi":"10.1096/fj.202403229R","DOIUrl":"10.1096/fj.202403229R","url":null,"abstract":"<p>Proper brain wiring relies on the precise distribution of axonal projections to specific subcellular domains of their target neurons. These spatially confined connections establish the anatomical foundation for neural circuit assembly. The mossy fiber (MF)–CA3 pathway in the hippocampus is an excellent system to study the mechanisms underlying lamina-specific connectivity. In rodents, MF projections develop postnatally and reach their mature configuration by the end of the second postnatal week. MF axons synapse on the proximal segments of the dendrites but avoid the somas of CA3 pyramidal neurons. As dentate gyrus granule neurons are continuously generated and integrated into the existing hippocampal circuit throughout the postnatal period and adulthood, the mechanisms that guide MF axons to achieve lamina-specific targeting of these later-born granule neurons remain unclear. Here, we show that deletion of the neurodevelopmental disorder-associated protein capicua (CIC) results in abnormal MF targeting in the mouse hippocampus. Notably, this defect emerges after the second postnatal week and persists into adulthood, distinguishing it from classical MF guidance defects, which typically manifest during the first postnatal week. We also demonstrate that this miswiring is due to CIC loss in dentate gyrus granule neurons rather than CA3 pyramidal neurons. Single-nucleus transcriptomics and trajectory analysis reveal a loss of a mature granule neuron subtype and dysregulation of axon guidance genes that are normally downregulated as granule neurons mature. Our findings uncover a previously unrecognized role for CIC in hippocampus development and offer insights into the regulation of lamina-specific MF connectivity in the postnatal brain.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403229R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111243","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":"A Novel Mechanism of Chlorogenic Acid in Cardioprotection: Blocking NLRP3 Inflammasome via Ca2+/CaMKIIα Signaling in Sepsis-Induced Cardiomyopathy","authors":"Huadong Meng,&nbsp;Kegong Chen,&nbsp;Zhonghua Lu,&nbsp;Weili Yu,&nbsp;Xinyi Hu,&nbsp;Hanqing Xu,&nbsp;Shusheng Zhou,&nbsp;Song Peng,&nbsp;Xiaohui Guo,&nbsp;Yun Sun","doi":"10.1096/fj.202502567RR","DOIUrl":"10.1096/fj.202502567RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, characterized by myocardial inflammation, oxidative stress, and cardiac dysfunction. Chlorogenic acid (CGA), a natural polyphenol with known anti-inflammatory and antioxidant properties, is abundant in many traditional medicinal plants used for cardiovascular and inflammatory disorders. However, its cardioprotective effects in SICM and the underlying mechanisms remain unclear. An in vivo cecal ligation and puncture (CLP) model was used to induce SICM in rats, followed by CGA treatment. Cardiac function and myocardial injury markers were assessed, while NLRP3 inflammasome activation and CaMKIIα involvement were investigated using molecular docking, gene overexpression, and site-directed mutagenesis. H9c2 cardiomyocytes were treated with lipopolysaccharide (LPS) and hypoxia/reoxygenation (H/R) to establish an in vitro SICM model. Mitochondrial function and pyroptosis were evaluated using oxygen consumption rate (OCR), extracellular acidification rate (ECAR), scanning electron microscopy (SEM), and key protein expression analysis. CGA improved cardiac function, reduced myocardial injury markers, and alleviated inflammation and fibrosis in SICM rats. CGA (25 μM) improved H9c2 cell viability in LPS + H/R-induced SICM by reducing LDH, CK-MB, and cTnT levels and suppressing inflammation, oxidative stress, and pyroptosis. It preserved mitochondrial function and cristae structure. Molecular docking and functional studies confirmed CGA binds to CaMKIIα and NLRP3, inhibiting inflammasome activation via the Ca²⁺/CaMKIIα pathway. Mutation of the GLU60 binding site abolished CGA's protective effects both in vitro and in vivo. CGA ameliorates SICM by suppressing NLRP3 inflammasome activation and pyroptosis through the Ca²⁺/CaMKIIα pathway. These findings offer new insights into CGA's cardioprotective effects and highlight its potential as a therapeutic agent for SICM.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088037","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":"CYP1B1 Mediates Cigarette Smoke–Induced Lipid Accumulation in Alveolar Type 2 Cells","authors":"Yin Zhu,&nbsp;Siddhika Gamare,&nbsp;Francesca Polverino,&nbsp;Caroline A. Owen,&nbsp;Payaningal R. Somanath,&nbsp;Xiaoyun Wang,&nbsp;Duo Zhang","doi":"10.1096/fj.202501439RR","DOIUrl":"10.1096/fj.202501439RR","url":null,"abstract":"<p>Alterations in lipid profiles have been shown in patients with chronic obstructive pulmonary disease (COPD), but the underlying molecular mechanisms remain unclear. In this study, we aimed to investigate the role of cytochrome P450 family-1 subfamily B member 1 (CYP1B1) in cigarette smoke (CS)-induced lipid accumulation in alveolar type II epithelial (AT2) cells. We observed a steady increase in CYP1B1 protein levels in AT2 cells from COPD patients. Additionally, CS exposure induced CYP1B1 expression in AT2 cells of murine lungs. In vitro, treatment with cigarette smoke extract (CSE) not only upregulated CYP1B1 expression but also triggered lipid accumulation in AT2-like cells. Functionally, overexpression of CYP1B1 promoted lipid accumulation in A549 and MLE-12 cells. Consistently, siRNA-mediated CYP1B1 inhibition significantly reduced CSE-induced lipid accumulation in AT2-like cells. Furthermore, treatment with 2,3′,4,5′-tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor, reduced CSE-induced lipid accumulation. TMS also attenuated CSE-induced mitochondrial reactive oxygen species production and cell apoptosis. Taken together, our findings suggest that CYP1B1 is upregulated by CS exposure and plays a key role in CS-induced lipid accumulation in AT2 cells. Targeting CYP1B1 may offer a potential therapeutic strategy for addressing lipid dysregulation and lung pathology in patients with COPD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501439RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087747","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":"Fabkin Promoted Osteoclasts Mature and Bone Loss in OVX-Induced Osteoporosis Mice","authors":"Chenhao Pan,&nbsp;Shixun Li,&nbsp;Changchun Li,&nbsp;Wing Cheuk Ko,&nbsp;Taihe Liu,&nbsp;Haoxian Liu,&nbsp;Donghao Guo,&nbsp;Yue Ding","doi":"10.1096/fj.202501946R","DOIUrl":"10.1096/fj.202501946R","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoporosis (OP) is a chronic skeletal disorder characterized by reduced bone mineral density and increased fracture risk, particularly from hip fractures linked to a 20%–24% increased mortality risk within the first year. Current therapies remained inadequate in addressing metabolic drivers, which prompted exploration of novel targets. Fabkin, a recently identified hormonal complex comprising fatty acid-binding protein 4 (FABP4), nucleoside diphosphate kinase (NDPK), and adenosine kinase (ADK), was implicated in metabolic and inflammatory signaling. It was suggested that Fabkin could promote Ca²⁺ influx and the release of inflammatory factors via the PKA pathway. However, its role in bone loss remained unclear. To investigate the role of Fabkin in OP, an ovariectomy (OVX)-induced murine model was used to simulate estrogen-deficient osteoporosis. FABP4-KO mice were generated to disrupt Fabkin formation, and bone microarchitecture was assessed using micro-CT and histological staining. Osteoclastogenesis assays in vitro were conducted using bone marrow-derived macrophages (BMDMs) treated with recombinant Fabkin components. Western blotting and RT-qPCR were performed to analyze key signaling pathways involved in osteoclast differentiation, particularly MAPK and NF-κB. Immunofluorescence analysis revealed an increase in Fabkin expression in the bone marrow of OVX mice. OVX-induced osteoporosis was significantly attenuated in FABP4-KO mice with higher BMD. TRAP staining showed a reduction in osteoclast numbers in FABP4-KO mice. In vitro, Fabkin treatment significantly enhanced osteoclast differentiation and bone resorption, whereas FABP4 deficiency inhibited osteoclast formation. Molecular analysis revealed that Fabkin promoted osteoclastogenesis via the RANKL-induced MAPK and NF-κB signaling pathways. These findings suggested that FABP4 might directly exacerbate osteoclastogenesis by acting as a Fabkin complex instead of a lipid regulator.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082103","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":"PTBP1 Reduces KLF9 mRNA Stability and Upregulates FUBP1 to Promote Colorectal Cancer Stemness and Cisplatin Resistance","authors":"Yan Liang,&nbsp;Yan Cao,&nbsp;Yuxuan Sun,&nbsp;Jiali Zhong,&nbsp;Yongliang Du,&nbsp;Le Liu,&nbsp;Xinyuan Hu,&nbsp;Jian Li,&nbsp;Gang Zhang","doi":"10.1096/fj.202403371R","DOIUrl":"10.1096/fj.202403371R","url":null,"abstract":"<div>\u0000 \u0000 <p>The emergence of chemoresistance leads to poor prognosis in colorectal cancer (CRC), and tumor stem cells play an essential role in tumor chemosensitivity. This work delved into the molecular mechanisms by which PTBP1 regulates CRC cell stemness and cisplatin (DDP) resistance. Clinical tissue samples originated from patients with CRC and DDP-resistant CRC. HT-29 and HCT116 cells were treated with DDP to establish DDP-resistant CRC cell lines. CCK-8, clone formation, and sphere formation assays were utilized to detect cell proliferative capacity and stemness, respectively. Chromatin immunoprecipitation, dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down were conducted to validate the interactions among PTBP1, FUBP1, and KLF9. A CRC DDP-resistant nude mouse model was developed for in vivo experiments. PTBP1 and FUBP1 were upregulated, while KLF9 was downregulated in DDP-resistant CRC cells and tissues. Knockdown of FUBP1 abolished CRC cell stemness and DDP chemoresistance in vivo and in vitro. KLF9 interacted with the FUBP1 promoter region to repress FUBP1 transcription. PTBP1 reduced KLF9 mRNA stabilization by binding to KLF9 mRNA, which promoted CRC cell stemness and DDP chemoresistance. PTBP1 reduced the stability of KLF9 mRNA, thereby relieving the transcriptional inhibition of FUBP1 by KLF9, leading to the development of stemness and DDP chemoresistance in CRC cells.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082254","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":"Human Umbilical Cord Mesenchymal Stem Cells Reduce Renal Tubular Epithelial Cell Apoptosis by Regulating the Wnt/β-Catenin Pathway in Diabetic Nephropathy","authors":"Yucan Guan,&nbsp;Weichen Nie,&nbsp;Xiaoying Bai,&nbsp;Huan Yang,&nbsp;Na Tian,&nbsp;Ping Nie","doi":"10.1096/fj.202501993R","DOIUrl":"10.1096/fj.202501993R","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetic nephropathy (DN), a leading cause of kidney failure, involves early renal tubular epithelial cell (TEC) apoptosis. This study investigated whether human umbilical cord-derived mesenchymal stem cells (hUCMSCs) protect against DN-related TEC apoptosis by modulating the Wnt/β-catenin signaling pathway. A Type 2 diabetic rat model was established using a high-fat diet and streptozotocin injection. hUCMSCs were administered intravenously. In vitro, HK11 cells were treated with high glucose and palmitate (HG/P), with or without hUCMSCs and the Wnt/β-catenin agonist SKL2001. Apoptosis, mitochondrial function, and oxidative stress were assessed by Annexin V-FITC/PI, JC-1, ROS staining, and Western blotting. Pathway activation was evaluated by immunoblotting, immunohistochemistry, and immunofluorescence. hUCMSCs alleviated renal tubular injury and reduced TEC apoptosis in diabetic rats. In vitro, hUCMSCs mitigated HG/P-induced ROS accumulation, mitochondrial dysfunction, and apoptosis, accompanied by upregulation of Bcl-2 and downregulation of Bax and cleaved caspase-3. Mechanistically, hUCMSCs suppressed HG/P-induced activation of Wnt/β-catenin signaling, as evidenced by decreased β-catenin nuclear accumulation and reduced Wnt5a expression, together with restoration of p-GSK3β levels. Co-treatment with the Wnt/β-catenin agonist SKL2001 reversed these molecular changes and partially attenuated the anti-apoptotic effects of hUCMSCs. hUCMSCs protect TECs from HG/P-induced apoptosis by inhibiting the Wnt/β-catenin pathway.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082141","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 AhR Is a Critical Regulator of the Pulmonary Response to Cannabis Smoke","authors":"Emily T. Wilson,&nbsp;Roham Gorgani,&nbsp;Nicole S. Heimbach,&nbsp;Alexandra Bartolomucci,&nbsp;Thupten Tsering,&nbsp;Julia V. Burnier,&nbsp;David H. Eidelman,&nbsp;Carolyn J. Baglole","doi":"10.1096/fj.202501533R","DOIUrl":"10.1096/fj.202501533R","url":null,"abstract":"<p>Cannabis use is prevalent worldwide, with smoking being the most common method of consumption. When smoking cannabis, users are exposed to both harmful combustion products and cannabinoids. The aryl hydrocarbon receptor (AhR), a transcription factor activated by both cannabinoids and combustion products, is known to regulate pulmonary responses to environmental insults. Therefore, we hypothesized that AhR activation would reduce susceptibility to the harmful effects of inhaled cannabis smoke. To investigate this hypothesis, <i>Ahr</i>^+/− and <i>Ahr</i>^−/− mice were exposed to air or cannabis smoke using a controlled puff regimen over a three-day period. In the first study to characterize the effects of cannabis smoke on lung tissue and the pulmonary secretome, we show that cannabis smoke activates AhR in lung tissue, leading to distinct immunological and proteomic responses across lung tissue, extracellular vesicles (EVs), and bronchoalveolar lavage fluid (BALF). AhR deficiency exacerbated neutrophilic inflammation, epithelial barrier disruption, and caused systemic cytokine elevation. Proteomic profiling revealed that AhR drives the activation of detoxification and metabolic pathways in lung tissue while suppressing cytoskeletal and adhesion proteins in response to cannabis smoke. In contrast, AhR loss shifted the proteomic response in EVs and BALF, altering coagulation, protease regulation, and metabolic stability. These findings demonstrate that AhR coordinates compartment-specific responses to cannabis smoke and plays a central role in preserving lung homeostasis and restraining inflammatory injury following cannabis exposure. These findings highlight not only the detrimental effects of cannabis smoke on lung health but also the pivotal role of the AhR as a key regulator of the pulmonary response to cannabis smoke exposure.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082177","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":"Expression and Clinical Implications of LAG-3 in Small Cell Lung Cancer","authors":"Liangdong Sun,&nbsp;Junjie Hu,&nbsp;Jue Wang,&nbsp;Xinsheng Zhu,&nbsp;Yilv Yan,&nbsp;Shiyue Wan,&nbsp;Huansha Yu,&nbsp;Gening Jiang,&nbsp;Lele Zhang,&nbsp;Haiyang Hu,&nbsp;Jing Zhang,&nbsp;Peng Zhang","doi":"10.1096/fj.202502183R","DOIUrl":"10.1096/fj.202502183R","url":null,"abstract":"<div>\u0000 \u0000 <p>The PD-L1 immune checkpoint inhibitors (ICIs) improve the survival in small cell lung cancer (SCLC), yet only a small subset experiences durable responses, possibly due to less than 20% of SCLC expressing PD-L1 &gt; 1% of tumor cells. Evaluating the expression of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to ICIs. We firstly evaluated 28 immune checkpoint molecules via RNA-seq data in the Cancer Cell Line Encyclopedia database. Next, our in-house proteogenomic dataset and other publicly available datasets, including microarray data, RNA-seq data, and scRNA-seq data from tumor specimens, were enrolled. IMpower133 and Roper et al. datasets were employed to evaluate LAG-3 as a predictive marker of immunotherapy efficacy in SCLC. Finally, Immunohistochemistry was performed to verify LAG-3 expression in SCLC. LAG-3 exhibited higher expression in SCLC cell lines than in lung adenocarcinoma, lung squamous cell carcinoma, and melanoma. Analysis of SCLC tumor and paired normal samples revealed the highest overexpression of LAG-3 in SCLC tumors among compiled checkpoint molecules. Higher LAG-3 expression correlated with longer overall survival and served as an independent favorable prognostic factor. Furthermore, higher LAG-3 expression was associated with increased MHC-I expression, immune cell infiltration, and certain immune checkpoints' expression. Increased LAG-3 expression correlated with ICI benefit in SCLC patients. scRNA-seq analysis revealed that LAG-3 was primarily expressed in the tumor cells and T cells, and LAG-3 expression was higher than that of PD-1, CD274, and CTLA-4 on the CD8⁺ T cells. LAG-3 might serve as a potential biomarker in SCLC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082027","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":"ARIH1 Promotes Preeclampsia by Inducing MFN2-Dependent Hypoxia-Triggered Mitophagy and Endoplasmic Reticulum Stress in Trophoblasts","authors":"Hongyu Liu,&nbsp;Yali Deng,&nbsp;Mei Peng,&nbsp;Yanting Nie,&nbsp;Jingfei Chen","doi":"10.1096/fj.202500821R","DOIUrl":"10.1096/fj.202500821R","url":null,"abstract":"<div>\u0000 \u0000 <p>The pathogenesis of preeclampsia (PE) involves endoplasmic reticulum stress (ERS) and the subsequent induction of mitophagy. Ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) is a key factor regulating mitophagy, but its role in PE has not been reported. In this study, we aimed to analyze the role of ARIH1 in the pathogenesis of PE. The role of ARIH1 in the pathogenesis of PE was investigated in a PE rat model and in an in vitro hypoxia/reoxygenation (H/R) model using HTR8 trophoblast cells. The study revealed that ARIH1 was upregulated while Mitochondrial fusion protein 2 (MFN2) was downregulated in PE rats and H/R-treated HTR8 cells. Inhibition of ARIH1 reversed the suppressed proliferation and invasion capacities of HTR8 cells under H/R conditions, reduced intracellular reactive oxygen species (ROS) and calcium ions (Ca²⁺), and modulated the protein expression of LC3II/LC3I, p62, glucose-regulatory protein 78 (GRP78), and C/EBP homologous protein (CHOP). Additionally, mitochondrial membrane potential was improved. Interestingly, treatment with Tunicamycin or Thapsigargin could reverse the inhibitory effects of ARIH1 downregulation on trophoblastic cells by activating endoplasmic reticulum stress (ERS) and mitophagy. Notably, the study identified for the first time that ARIH1 mediates the ubiquitination degradation of MFN2. Inhibition of MFN2 abolished the regulatory effects of ARIH1 downegulation on ERS and mitophagy in trophoblast cells, as well as the associated damage in PE rats. Overall, the findings underscore the crucial role of ARIH1 in regulating mitophagy and ERS through MFN2, highlighting its significance in the pathogenesis of PE.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081797","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":"From Bench to Clinic: Advances in Anti-Inflammatory Therapies for Atherosclerotic Coronary Artery Disease","authors":"Kan Wang,&nbsp;Zheng Yin,&nbsp;Yang Zhang,&nbsp;Xianpeng Wu,&nbsp;Lin Fan","doi":"10.1096/fj.202502269R","DOIUrl":"10.1096/fj.202502269R","url":null,"abstract":"<p>Atherosclerosis (AS) is a chronic, progressive inflammatory disorder characterized by the deposition of lipid-laden plaques, infiltration of immune cells, and remodeling of vascular structures within arterial walls. It remains the primary pathological driver of atherosclerotic coronary artery disease (ASCAD) and a major contributor to global mortality. While conventional lipid-lowering therapies, particularly statins, have significantly reduced the incidence of ASCAD by targeting hyperlipidemia, a considerable residual inflammatory risk continues to exist. This unresolved inflammation exacerbates plaque vulnerability, increases the likelihood of rupture, and precipitates thrombotic complications. Recent breakthroughs in understanding the complex inflammatory mechanisms underlying AS, including endothelial dysfunction, macrophage polarization, T-cell activation, and the release of pro-inflammatory cytokines, have revealed novel therapeutic targets. This mechanistic insight has spurred the development of innovative anti-inflammatory strategies, including monoclonal antibodies targeting specific cytokines (e.g., IL-1β, TNF-α), epigenetic modulators, and immune-based interventions. This review synthesizes the current understanding of the inflammatory pathogenesis of AS, evaluates the translational potential of emerging anti-inflammatory therapies, and discusses the challenges in optimizing the balance between efficacy and safety. By bridging discoveries in basic science with clinical applicability, this analysis aims to guide future research and foster therapeutic innovations in combating ASCAD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082092","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}