The FASEB Journal最新文献

{"title":"FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6","authors":"Qian Zhang,&nbsp;Yuqin Zha,&nbsp;Xiaoting Wang,&nbsp;Peishen Zhao,&nbsp;Owen L. Woodman,&nbsp;Mi Zhou,&nbsp;Yuguo Chen,&nbsp;Xiaojun Zhou,&nbsp;Cheng Xue Qin","doi":"10.1096/fj.202501823R","DOIUrl":"10.1096/fj.202501823R","url":null,"abstract":"<p>Restenosis following endovascular intervention in lower extremity arterial disease contributes to significant morbidity and mortality. This study investigates the role of formylpeptide receptor 2 (FPR2) in neointimal hyperplasia and evaluates the therapeutic potential of the selective FPR2 agonist BMS-986235 in mitigating restenosis. FPR2 expression was significantly reduced in the popliteal and anterior tibial arteries of male amputees with restenosis compared to healthy controls. Whole-body and myeloid-specific FPR2 knockout mice consistently displayed exaggerated neointimal hyperplasia, accompanied by a marked reduction in vessel lumen diameter, following endothelial injury. Treatment with BMS-986235 effectively slowed the progression of restenosis. Mechanistically, FPR2 activation maintained the differentiated state of vascular smooth muscle cells (VSMCs) and limited excessive M2 macrophages accumulation, thereby limiting neointimal remodeling. Transcriptomic analysis additionally identified ELOVL fatty acid elongase 6 (ELOVL6) as a novel downstream target of FPR2 activation, which was upregulated in restenosis models. Notably, BMS-986235 reduced ELOVL6 expression in both macrophages and VSMCs, inhibiting VSMC proliferation and mitigating neointimal hyperplasia. FPR2 activation mitigates restenosis progression by preserving VSMC differentiation through the FPR2/ELOVL6 axis, highlighting its potential as a novel therapeutic target for prevention of restenosis.</p>","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":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501823R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999105","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":"Assessment of Myocardial Injury Size Metrics Using Carotid Pressure Waveform: Proof-of-Concept in Coronary Occlusion/Reperfusion Rat Model","authors":"Jiajun Li,&nbsp;Rashid Alavi,&nbsp;Wangde Dai,&nbsp;Ray V. Matthews,&nbsp;Robert A. Kloner,&nbsp;Niema M. Pahlevan","doi":"10.1096/fj.202502111R","DOIUrl":"10.1096/fj.202502111R","url":null,"abstract":"<p>Myocardial infarction (MI) is a leading cause of death worldwide and the most common precursor to heart failure, even after initial treatment. Precise evaluation of myocardial injury is crucial for assessing interventions and improving outcomes. Extensive evidence from both preclinical models and clinical studies demonstrates that the extent and severity of myocardial injury (i.e., myocardial infarct size, ischemic risk zone, and no-reflow area) are critical determinants of long-term outcomes post-MI. This study aims to assess whether carotid pressure waveforms, analyzed using an intrinsic frequency (IF)–machine learning (ML) approach, can accurately quantify myocardial injury sizes: myocardial infarct size, ischemic risk zone, and no-reflow area. Acute MI was induced in <i>N</i> = 88 Sprague-Dawley rats using a standard coronary occlusion/reperfusion model. MI-injury sizes were obtained via histopathology. IF metrics were extracted from carotid pressure waveforms post-MI. ML classifiers were developed using 66 rats and externally tested on 22 additional rats. Our best developed model for infarct size achieved an accuracy of 0.95 (specificity = 0.95, sensitivity = 0.96). For the ischemic risk zone, the best model showed an accuracy of 0.85 (specificity = 0.90, sensitivity = 0.80), and for the no-reflow area, we reached an accuracy of 0.88 (specificity = 0.89, sensitivity = 0.86). To conclude, a hybrid physics-based ML approach applied to carotid pressure waveforms successfully classified MI-injury severity. As carotid pressure waveforms can be measured non-invasively and remotely (e.g., via smartphones), this proof-of-concept preclinical study suggests a translational potential for post-MI management, enabling timely interventions, improved patient monitoring, and mitigating adverse outcomes.</p>","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":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202502111R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999106","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":"Whole-Gut Spatial Genomic Analysis Reveals Molecular Regionalization of the Differentiating Zebrafish Enteric Nervous System","authors":"Rodrigo Moreno-Campos,&nbsp;Nikhita S. Mummaneni,&nbsp;Rosa A. Uribe","doi":"10.1096/fj.202501470R","DOIUrl":"10.1096/fj.202501470R","url":null,"abstract":"<p>The enteric nervous system (ENS) is the intrinsic nervous system of the gut and controls essential functions, such as gut motility, intestinal barrier function, and water balance. The ENS displays a complex 3D architecture within the context of the gut and specific transcriptional states needed to control gut homeostasis. During development, the ENS develops from enteric neural progenitor cells (ENPs) that migrate into the gut and differentiate into functionally diverse neuron types. Incorrect ENS development can disrupt ENS function and induce various gut disorders, including the congenital disease Hirschsprung disease, or various other functional gut neurological disorders, such as esophageal achalasia. In this study, we used the zebrafish larval model and performed whole gut spatial genomic analysis (SGA) of the differentiating ENS at cellular resolution. To that end, a pipeline was developed that integrated early and late developmental ENS stages by linking various spatial and transcriptional dimensions to discover regionalized cellular groups and their co-expression similarity. We identified 3D networks of intact ENS surrounding the gut and predicted cellular connectivity properties based on the stage. Spatial variable genes, such as <i>hoxb5b</i>, <i>hoxa4a</i>, <i>etv1,</i> and <i>ret,</i> were regionalized along gut axes, suggesting they may have a precise spatiotemporal control of ENS development. The application of SGA to ENS development provides new insights into its cellular transcriptional networks and interactions and provides a baseline data set to further advance our understanding of gut neurodevelopmental disorders such as Hirschsprung disease and congenital enteric neuropathies.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501470R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999019","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":"Deficiency of Microglial Hv1 Protects Against Lipopolysaccharide-Induced Neuroinflammation via the NF-κB Signaling Pathway and HIF1α-Mediated Metabolic Reprogramming","authors":"Lingbin Sun,&nbsp;Xihua Wang,&nbsp;Shuyuan Guan,&nbsp;Ping Zhang,&nbsp;Dongling Chen,&nbsp;Tao Luo","doi":"10.1096/fj.202402271RRR","DOIUrl":"10.1096/fj.202402271RRR","url":null,"abstract":"<div>\u0000 \u0000 <p>Neuroinflammation plays a pivotal role in the initiation and progression of cognitive impairments. Hv1 channels have been implicated in proton extrusion, microglial activation, and neuroinflammation onset. Despite this, the specific mechanisms by which Hv1 deficiency mitigates neuroinflammation and its impact on pathophysiological processes are not fully understood. In this study, we investigated the role of Hv1 in LPS-induced hippocampal inflammation and cognitive deficits. Utilizing both knockout/knockdown and overexpression methodologies, we uncovered Hv1's contribution to neuroinflammatory processes. Our findings reveal that Hv1 loss exerts dual protective effects against LPS-induced neuroinflammation through NF-<i>κ</i>B-mediated cytokine production and PI3K/Akt/HIF1α-mediated aerobic glycolysis, as evidenced by RNA sequencing and metabolomics analysis. Given the pivotal function of NF-<i>κ</i>B in these responses, we observed a decrease in NF-<i>κ</i>B activation and a reduction in the production of pro-inflammatory mediators in microglia with Hv1 deficiency. Conversely, the luciferase reporter assay and EMSA revealed that Hv1 overexpression augments NF-<i>κ</i>B signaling. Furthermore, Hv1 deficiency resulted in reduced HIF1α expression and downregulation of its target genes, including HK2 and PFKFB3, thereby inhibiting aerobic glycolysis. In vivo results reveal a distinct microglial Hv1 role in regulating microglial metabolic reprogramming and neuroinflammation in cognitive deficits, suggesting Hv1 as a potential therapeutic target for neuroinflammation mediated by microglia, especially in the context of NF-<i>κ</i>B dysregulation. Our findings highlight the significance of targeting aerobic glycolysis in the regulation of cognitive impairments. Additionally, our research provides novel insights into Hv1's regulatory influence on neuroinflammation via NF-<i>κ</i>B signaling and metabolic reprogramming pathways.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999018","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":"Partial Deletion of the Carboxyl-Terminal Signal Sequence of the Cellular Prion Protein Alters Protein Expression via Endoplasmic Reticulum–Associated Degradation","authors":"Miryeong Yoo,&nbsp;Sungeun Lee,&nbsp;Jieun Kim,&nbsp;Sunyeong Cha,&nbsp;Min Young Lee,&nbsp;Yeon Jeong Hwang,&nbsp;Woo-Ri Ko,&nbsp;Taeeun Kim,&nbsp;A-ran Kim,&nbsp;Trang H. T. Trinh,&nbsp;Young-Mi Kim,&nbsp;Yong-Pil Cheon,&nbsp;Chongsuk Ryou","doi":"10.1096/fj.202501227RR","DOIUrl":"10.1096/fj.202501227RR","url":null,"abstract":"<p>Cellular prion protein (PrP^C) is a glycoprotein tethered to the plasma membrane via a GPI-anchor, and it plays a crucial role in prion diseases by undergoing conformational change to PrP^Sc. To generate a knock-in (KI) mouse model expressing bank vole PrP^C (BVPrP^C), a KI targeting construct was designed. However, a <i>Prnp</i> gene sequence that encodes PrP^C lacking seven C-terminal amino acid residues of the GPI-anchoring signal sequence (GPI-SS) was unintentionally introduced into the construct. The resulting KIBVPrP248 mice exhibited very low PrP^C expression and resistance to prion infection. To investigate the underlying mechanism of reduced PrP^C expression, RK13 cells expressing either full-length GPI-SS (BVPrP255) or truncated GPI-SS (BVPrP248) and KIBVPrP248 mice were analyzed. In RK13-BVPrP248 cells, PrP^C protein levels were nearly ten-fold lower than in RK13-BVPrP255 cells, mimicking the extremely low PrP^C expression of the KIBVPrP248 mice. The abundance, stability, and translational efficiency of the <i>Prnp</i> mRNA were not the primary causes for the low PrP^C expression in RK13-BVPrP248 cells. A pharmacological analysis revealed that BVPrP248 underwent enhanced degradation via the ER-associated degradation pathway, with increased PrP ubiquitination detected in both the cell and animal models. An immunofluorescence analysis showed that BVPrP248 was mislocalized to the ER, co-localizing with Grp78, an ER chaperone. Although mislocalization of BVPrP248 under the transient overexpression condition led to mild activation of the unfolded protein response in RK13-BVPrP248 cells, low-level chronic expression of BVPrP248 in stable transfectants and KIBVPrP248 mice did not facilitate such events. These findings suggested that the C-terminal GPI-SS of PrP^C plays a critical role in PrP^C biogenesis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501227RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934829","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 Systems Biology Perspective on Childhood ADHD: Neurochemical Dysregulation, Brain-Behavior Interactions, and Emerging Therapeutics","authors":"Norah Suliman Alsoqih,&nbsp;Elsayed A. Elmorsy,&nbsp;Rasha Abu-Khudir,&nbsp;Sameh Saber,&nbsp;Noha Keshk,&nbsp;Fatma Elnaghy,&nbsp;Rabab S. Hamad,&nbsp;Attalla F. El-kott,&nbsp;Sally Negm,&nbsp;Mohammed A. AlShehri,&nbsp;Mohamed A. M. Ali,&nbsp;Mustafa Ahmed Abdel-Reheim,&nbsp;Alshaimaa A. Farrag,&nbsp;Hanan Eissa,&nbsp;Ahmed Gaafar,&nbsp;Mahmoud E. Youssef","doi":"10.1096/fj.202501829RR","DOIUrl":"10.1096/fj.202501829RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Attention deficit hyperactivity disorder (ADHD) is a pervasive neurodevelopmental condition that typically manifests during childhood. Its symptoms manifest much earlier—often before the age of seven. With the disorder's continuous patterns of inattention, hyperactivity, and impulsiveness, it gets in the way of academic, social, and occupational performance. Individuals affected by ADHD are found among all age groups, though its presentation may change over time. The mechanisms of ADHD seem to be very complex and multifactorial and include disturbances within neuroanatomical structures, neurochemical systems, and developmental trajectories. These influences create the characteristic behavior and cognitive profiles of an individual with ADHD that substantiate the heterogeneity of the disorder. This review will be centered on biology and development regarding ADHD, with contributions from modern scientific research. It will also delve into novel pharmacological therapeutic approaches for the management of ADHD.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501829RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935369","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":"Incidence and Risk Factors for Progression of Acute Kidney Injury to Chronic Kidney Disease After Liver Transplantation: A Retrospective Cohort Study","authors":"Liping Li,&nbsp;Jinxuan Dai,&nbsp;Yiqian Liu,&nbsp;Siyang Zeng,&nbsp;Jing Yang,&nbsp;Xiaoyun Li,&nbsp;Yanling Wang,&nbsp;Weifeng Yao,&nbsp;Chenfang Luo,&nbsp;Chaojin Chen","doi":"10.1096/fj.202500546R","DOIUrl":"10.1096/fj.202500546R","url":null,"abstract":"<p>Acute kidney injury (AKI) following liver transplantation has the potential to progress to chronic kidney disease (CKD), which can result in extended hospital stays, elevated healthcare costs, and increased mortality rates. This retrospective cohort study seeks to examine the prognosis of AKI progression to CKD post-liver transplantation and to identify its independent risk factors. A cohort of 443 patients who developed AKI post-liver transplantation was analyzed, with participants categorized into a CKD group and a non-CKD group. The progression of AKI to CKD was observed in 29.3% (130 out of 443) of cases. Patients who developed CKD exhibited a significantly higher 1-year mortality rate of 4.6% (<i>p</i> = 0.004). Multivariate logistic regression analysis identified several independent risk factors for the progression from AKI to CKD, including preoperative diabetes (odds ratio [OR] 2.62; 95% confidence interval [CI] 1.32, 5.21), hepatic malignancy (OR 1.95; 95% CI 1.06, 3.57), elevated preoperative serum creatinine (SCr) levels (OR 1.02; 95% CI 1.01, 1.03), transition from postoperative AKI to acute kidney disease (AKD) (OR 3.99; 95% CI 1.94, 8.23), AKD stages 2 and 3 (OR 2.48; 95% CI 1.33, 4.61), and an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² within 30 days (OR 3.03; 95% CI 1.70, 5.40). Conversely, higher preoperative hematocrit (HCT) levels (OR 0.00; 95% CI 0.00, 0.26) and recovery from AKD (OR 0.49; 95% CI 0.27, 0.86) were associated with a reduced risk of progression from postoperative AKI to CKD. The progression of AKI to CKD following liver transplantation is independently associated with preoperative diabetes, hepatic malignancy, elevated preoperative SCr levels, postoperative transition from AKI to AKD, AKD stages 2 and 3, and an eGFR of less than 60 mL/min/1.73 m² within 30 days.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500546R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934831","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":"Altered Gating of Two CaV2.1 Variants Linked to Neurodevelopmental Disorders With Epilepsy and Migraine","authors":"Ulises Meza,&nbsp;Catalina Romero-Méndez,&nbsp;Danira A. Ramírez-De León,&nbsp;Hugo Bibollet,&nbsp;Sidharth Tyagi,&nbsp;Pradnya Bhadane,&nbsp;Symeon Papadopoulos,&nbsp;Mario F. Salamanca-Vera,&nbsp;Jose Manuel Perez-Aguilar,&nbsp;Michael F. Wangler,&nbsp;Roger A. Bannister","doi":"10.1096/fj.202501708R","DOIUrl":"10.1096/fj.202501708R","url":null,"abstract":"<div>\u0000 \u0000 <p>P/Q-type (Ca_V2.1) Ca²⁺ channels regulate the release of neurotransmitter at central synapses. Missense and nonsense mutations in <i>CACNA1A</i>, the gene that encodes the principal α_1A subunit of the Ca_V2.1 channel complex, are well-known to cause Episodic Ataxia type 2 (EA2) and Familial Hemiplegic Migraine type 1 (FHM1). These Ca_V2.1 channelopathies are typically caused by either channel loss/reduction-of-function (LOF) or gain-of-function (GOF), respectively. However, recent genome-wide sequencing has revealed that point mutations in Ca_V2.1, in fact, underlie a spectrum of neurological disorders that feature epilepsy, tremor, nystagmus, hypotonia, cerebellar atrophy, cognitive deficits, and global developmental delay. Given the multiple manifestations of the mutations and the broad range of severity among these disorders, the assessment of the impact of an individual pathological mutation on channel function is essential for understanding the etiology of a given case. To this end, we expressed the rat orthologues of one newly identified and one previously reported, but yet to be characterized, human Ca_V2.1 variants (V176M and R1673C, respectively) in HEK 293 cells and investigated their biophysical properties using patch-clamp electrophysiology. The corresponding rat variants (V178M and R1624C, respectively) had multiple effects on channel function, though each mutation affected channel gating differently. V178M displayed a ~10 mV hyperpolarizing shift in activation and slowed deactivation, while R1624C slowed channel activation kinetics, delayed closure, and accelerated recovery from inactivation. Molecular modeling revealed structural alterations that may account for the observed changes in channel gating. Taken together, our results indicate that V176M and R1673C likely cause human Ca_V2.1 channelopathies through multiple, distinct mechanisms.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935368","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":"MIG-6 Plays a Critical Role as a PGR Mediator in Maintaining Epithelial and Stromal Cells for Uterine Receptivity","authors":"Dinh Nam Tran,&nbsp;Shamsun Nahar,&nbsp;Jung-Yoon Yoo,&nbsp;HyeJoo An,&nbsp;Md Saidur Rahman,&nbsp;Sohyeon Yun,&nbsp;Rong Li,&nbsp;Steven L. Young,&nbsp;Bruce A. Lessey,&nbsp;Tae Hoon Kim,&nbsp;Jae-Wook Jeong","doi":"10.1096/fj.202501455R","DOIUrl":"10.1096/fj.202501455R","url":null,"abstract":"<div>\u0000 \u0000 <p>Ovarian steroid hormones—estrogen and progesterone—play a central role in regulating epithelial-stromal interactions in the uterus. These interactions are critical for uterine function, including endometrial receptivity, implantation, and decidualization. These interactions involve complex signaling crosstalk between the uterine epithelium and the underlying stroma, with dynamic cell population-specific roles. Mitogen-inducible gene 6 (MIG-6) is a key mediator of progesterone signaling in the endometrium, and loss of MIG-6 results in implantation failure due to a non-receptive endometrium. To investigate whether MIG-6 deficiency disrupts the complex and dynamic cell population-specific roles of uterine cells, we performed single-cell RNA sequencing to characterize the cellular composition and functional alterations in the non-receptive endometrium of uterine-specific <i>Mig-6</i> knockout (<i>Pgr</i>^<i>cre/+</i><i>Mig-6</i>^<i>f/f</i>; <i>Mig-6</i>^<i>d/d</i>) mice. Compared to control mice, <i>Mig-6</i>^<i>d/d</i> mice exhibited distinct gene expression patterns in both endometrial epithelial and stromal cells. We identified dysregulation of <i>Egr1</i> in the non-receptive endometrium along with attenuated expression of <i>Foxa2</i> and <i>Cyp26A1</i> in epithelial cells of <i>Mig-6</i>^<i>d/d</i> mice. Notably, LRP2 expression was diminished in epithelial cells of both <i>Mig-6</i>^<i>d/d</i> mice and infertile women with endometriosis. These findings demonstrate that MIG-6 is a critical progesterone receptor (PGR) mediator that maintains endometrial epithelial and stromal cell function essential to uterine receptivity. Our study advances the understanding of the molecular pathways underlying endometrial receptivity and provides a foundation for therapeutic strategies to improve pregnancy outcomes.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934830","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 Pathophysiological Functions of Heparanases: From Evolution, Structural and Tissue-Specific Perspectives","authors":"Elham Vahdatahar,&nbsp;Clément Daviaud,&nbsp;Hugo Main,&nbsp;Rachel Havret,&nbsp;Claire Debarnot,&nbsp;Laure Favot-Laforge,&nbsp;Jean-François Jégou,&nbsp;Ingrid Fruitier-Arnaudin,&nbsp;Antoine Dufour,&nbsp;Romain Vivès,&nbsp;Franck Morel,&nbsp;Yves Bourne,&nbsp;Kévin Baranger","doi":"10.1096/fj.202501859R","DOIUrl":"10.1096/fj.202501859R","url":null,"abstract":"<p>Heparanase 1 (HPSE1) is a unique endoglycosidase responsible for the enzymatic cleavage of heparan sulfate, thereby playing important functions in cancer processes. In contrast, the structurally related Heparanase 2 (HPSE2) lacks catalytic activity and appears to counteract HPSE1 activities. However, contradictory observations in various pathologies highlight the need for a better understanding of the respective contributions of both heparanases. In this review, we provide a comprehensive resource about the biology of HPSE1 and HPSE2 based on findings from different mouse models, with an emphasis on immune cells and their involvement in skin pathophysiology. In addition, we explore the evolutionary relationships between the two heparanases and describe the structure–function of HPSE2 using the advanced protein-prediction tool AlphaFold 3 (AF3). These approaches unveil new insights for deciphering the functional molecular determinants that distinguish HPSE1 from HPSE2.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501859R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930096","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}