FASEB bioAdvances最新文献

{"title":"<i>APOE4</i> Drives Sex- and Diet-Dependent Effects on AD-Like Pathology, Cognition, and Mitochondrial Function.","authors":"Chelsea N Johnson, Colton R Lysaker, Xin Cao, Vivien Csikos, Frederick Boakye, Paul J Kueck, Edziu Franczak, Paige C Geiger, Jill K Morris, John P Thyfault, Heather M Wilkins","doi":"10.1096/fba.2026-00121","DOIUrl":"https://doi.org/10.1096/fba.2026-00121","url":null,"abstract":"<p><p>Apolipoprotein E4 (<i>APOE4</i>) is the strongest genetic risk factor for Alzheimer's disease (AD), yet it's unclear how this allele promotes disease. While factors like diet and sex may modify AD susceptibility in <i>APOE4</i> carriers, the interaction between these factors is poorly understood. Here, we sought to determine if <i>APOE4</i>, sex, and diet interact to influence AD related outcomes in mice. Male and female <i>APOE3</i> and <i>APOE4</i> targeted replacement (TR) mice were fed a low-fat diet or high-fat diet from 4 to 8 months old. Serum neurodegenerative disease biomarkers, brain amyloid beta (Aβ), APOE, and tau, learning and memory, hippocampal mitochondrial function and proteomics data were collected. Serum GFAP and NfL were unaffected by <i>APOE4</i>, while HFD was associated with greater serum NfL and GFAP. Whole brain Aβ was significantly altered by sex, diet, and genotype. There was a main effect of genotype on levels of brain APOE with levels being lower in <i>APOE4</i> mice. <i>APOE4</i> TR mice also exhibited impaired learning before diet. Proteomic analysis revealed that <i>APOE4</i> exerts diet- and sex-dependent effects on mitochondrial pathways. This included downregulation of pyruvate metabolism in HFD males and oxidative phosphorylation in HFD females. Basal respiration was lower in <i>APOE4</i> versus <i>APOE3</i> TR females. We provide novel evidence that <i>APOE4</i> may drive early sex- and diet-dependent reductions in pathways that support brain mitochondrial energy metabolism.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 ","pages":"e70113"},"PeriodicalIF":2.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13146351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA 15a and 16 Regulate Proteostasis in Non-Small Cell Lung Cancer.","authors":"Patrick J Ryan, Bethany C Guerra, Peter Nghiem, Steven E Riechman, Mariana Janini Gomes, James D Fluckey","doi":"10.1096/fba.2026-00075","DOIUrl":"https://doi.org/10.1096/fba.2026-00075","url":null,"abstract":"<p><p>Aberrant anabolic activity is critical to tumor biology; however, much remains to be learned about the regulators of protein anabolism in cancer and how this regulation may affect cancer pathophysiology. MicroRNA (miRNA), a family of small nucleotide regulatory molecules, may serve as a potential source of proteostatic regulation. Here, we examined the ability of two co-transcribed miRNA species, miR15a and miR16 (jointly described as miR15a/16) to regulate protein handling and pathophysiology in non-small cell lung cancer (NSCLC). We found that miR15a/16 regulates genes in numerous metabolic and pathological pathways, including those related to protein metabolism. Transfection of cellular models of NSCLC with miR15a/16 mimetics caused reductions in both cell growth and protein synthesis rates. These findings indicate that miR15a/16 acts as regulators of protein anabolism in NSCLC, serving as novel metabolic regulators and potential clinical therapeutic targets for malignant lung cancer.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 ","pages":"e70111"},"PeriodicalIF":2.0,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network Analysis Identifies Microsomal Glutathione S-Transferase as a Potential Regulator of Oxidative Stress and Proteasome Dysfunction in Human Osteoarthritic Menisci.","authors":"Xinjie Wu, Amina Hamzatova, Cecilia Aulin, Wei Sun, Andre Struglics, David A Hart, Paul W Ackermann, Aisha S Ahmed","doi":"10.1096/fba.2025-00302","DOIUrl":"https://doi.org/10.1096/fba.2025-00302","url":null,"abstract":"<p><p>Osteoarthritis (OA)-related meniscal degeneration involves complex interactions between oxidative stress and proteasomal dysfunction. However, the molecular drivers of regional meniscal vulnerability remain poorly defined. This study integrated multiple transcriptomic datasets from OA and control menisci to identify functional networks and hub genes by using weighted gene co-expression network analysis. Human meniscal tissues from medial and lateral compartments were harvested during total knee arthroplasty and subjected to western blot analysis. In vitro assays on the basis of human chondrocytes were exposed to lipopolysaccharide or the proteasome inhibitor MG132 (carbobenzoxy-l-leucyl-l-leucyl-l-leucinal) to evaluate the stimulus-specific regulation of identified network and hub genes. Weighted gene co-expression network analysis revealed microsomal glutathione S-transferase (MGST1) as the hub gene within a module enriched for ubiquitination and proteasome activity. Experimental validation in human meniscal tissues demonstrated pronounced upregulation of MGST1, ubiquitin-conjugating enzyme E2 N (UBE2N), and proteasome activator complex subunit alpha (PSMA) in mechanically overloaded medial compartments compared to lateral regions. In vitro studies demonstrated stimulus-specific modulation: lipopolysaccharide-induced inflammatory stress upregulated MGST1, whereas proteasome inhibition via MG132 led to its downregulation. These findings highlight a dynamic interplay between redox adaptation and proteostasis, where chronic mechanical stress drives MGST1-mediated antioxidant responses and compensatory ubiquitination. Together, these results suggest that joint tissues dynamically adapt to mechanical and inflammatory challenges by modulating oxidative stress defenses and protein quality control mechanisms, processes central to OA pathophysiology.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 ","pages":"e70101"},"PeriodicalIF":2.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological Challenges for Ablation of BMPR1A in Hypothalamic Tanycytes-A Cautionary Tale.","authors":"Tianyi Tao, Noelle Leon-Palmer, Sabrina DiPietro, Kristy L Townsend","doi":"10.1096/fba.2025-00300","DOIUrl":"https://doi.org/10.1096/fba.2025-00300","url":null,"abstract":"<p><p>The hypothalamus coordinates energy-balance regulation and is also a neurogenic/plastic region in the adult brain. Tanycytes, a specialized population of radial glial-like cells lining the third ventricle, reside at the critical interface between the blood, cerebrospinal fluid, and hypothalamic parenchyma. This unique positioning enables them to sense metabolic and nutrient-derived signals, and to shuttle molecules between periphery and brain. Tanycytes can respond to glucose and lipids, as demonstrated by a calcium transient down their long processes that extend into the hypothalamic nuclei. Tanycytes are also capable of self-renewal and differentiation after brain injury, supporting their classification as putative neural stem cells in the adult hypothalamus. Bone morphogenetic protein (BMP) signaling regulates neuroplasticity and contributes to metabolic regulation, including appetite and sympathetic drive to adipose. We previously demonstrated that central administration of BMP7 suppresses appetite, and BMP receptor 1A (BMPR1A) in anorectic hypothalamic POMC neurons impacts appetite regulation. BMPR1A is also tightly and highly co-expressed in hypothalamic tanycytes. Here, we attempted to genetically inactivate BMPR1A in adult tanycytes to explore its functional roles. Using the Rax-CreER^T2xBMPR1Aflox mouse line, we tested multiple routes of tamoxifen administration, as well as its metabolite, without success. Cre recombinase activity was successfully induced via dietary tamoxifen (shown by recombination of the BMPR1A locus and fluorescent reporter induction), but efficient BMPR1A knockout in adult tanycytes was not achieved. Similarly, adeno-associated viral (AAV)-mediated BMPR1A knockdown via the Dio2 promoter and intracerebroventricular delivery yielded limited efficiency, despite confirmed Cre activity indicated by reporter expression. We also observed a compensatory increase in BMPR1A in cells not targeted by these knock-out/knockdown systems, as we observed previously with POMC-Cre knockout of BMPR1A, indicating a responsiveness of the hypothalamic niche to manipulation of BMPR1A levels. Together, our findings support that Cre-driven reporter activity doesn't guarantee gene depletion, and demonstrate that current strategies for loss of function of BMPR1A in adult hypothalamic tanycytes remain technically challenging and require careful validation before interpretation of phenotypes. More efficient and reliable methods are required to elucidate the molecular signaling and functional roles of molecules expressed in adult tanycytes.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 ","pages":"e70107"},"PeriodicalIF":2.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of Palmitoylethanolamide or Ibuprofen on the Abundance Profile and Synthesis Rate of Proteins in C2C12 Skeletal Myotubes.","authors":"Paige L Cole, Connor A Stead, Jatin G Burniston, Daniel J Owens","doi":"10.1096/fba.2025-00286","DOIUrl":"https://doi.org/10.1096/fba.2025-00286","url":null,"abstract":"<p><p>Palmitoylethanolamide (PEA) and ibuprofen (IBU) exert anti-inflammatory effects that may influence skeletal muscle adaptation; however, their impact on muscle proteome dynamics remains unclear. Dynamic proteome profiling was performed in differentiated C2C12 myotubes treated for 36 h with D₂O and either vehicle control (VC), PEA (10 μM), or IBU (100 μM). Protein-specific fractional synthesis rates (FSR; 1541 proteins) and relative protein abundances at 36 h (3085 proteins) were quantified and compared between treatments and VC. Relative to VC, PEA increased synthesis rates of 101 proteins (<i>p</i> < 0.05), whereas 2 proteins exhibited reduced synthesis. IBU increased synthesis rates of 165 proteins and reduced 7 proteins relative to VC. Both PEA and IBU increased total ribosomal protein synthesis (~80% relative to VC) and increased the abundance of 40S ribosomal subunit proteins (~18% relative to VC at 36 h). In addition, IBU treatment was associated with greater abundance of proteins involved in muscle contraction and extracellular matrix organization, reduced abundance of proteins associated with carbohydrate metabolism (21 proteins), and increased abundance of proteins linked to lipid metabolic pathways (17 proteins), relative to VC. In contrast, PEA-induced abundance differences were largely restricted to ribosomal proteins. These findings demonstrate that PEA and IBU enhance ribosomal protein turnover relative to control, whereas IBU elicits broader treatment-associated proteome remodeling.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":"e70108"},"PeriodicalIF":2.0,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Proteomics of Multiple Menstrual Symptoms in Female Athletes: A Pilot Study.","authors":"Kai Fushimi, Tasuku Kondo, Nodoka Ikegami, Mizuki Yamada, Sing Ying Wong, Mikako Sakamaki-Sunaga, Nobuhiro Hayashi","doi":"10.1096/fba.2026-00002","DOIUrl":"https://doi.org/10.1096/fba.2026-00002","url":null,"abstract":"<p><p>Menstrual symptoms, including primary dysmenorrhea and premenstrual syndrome, are significant problems affecting women's health condition. However, their biological functions are still unclear. The objective of this study was to elucidate proteins related to menstrual symptoms with high-performance two-dimensional gel electrophoresis (2DE). Serum samples were collected once a week over 5 weeks. At the same time, 46 types of menstrual symptoms were evaluated using a menstrual distress questionnaire (MDQ) on a scale of 0-4 (0: not at all, closer to 4: very strongly). 2DE images were obtained from the serum of participants with continuous menstrual phases, including the luteal, menstrual, and follicular phases. Multiple regression analysis was conducted to identify proteins that change in response to the interaction between menstrual phase and menstrual symptoms. As a result, six symptoms were associated with specific proteins (muscle stiffness with serine protease-1; general aches and pains with junction plakoglobin; tension with transferrin, ceruloplasmin, and desmoglein; depression with kininogen-1; distractibility with dermcidin; take naps; stay in bed with transferrin and hemopexin). These results indicate that various menstrual symptoms may have different underlying mechanisms. Further research into these proteins may lead to novel understanding of menstrual symptoms and support more effective health management for women.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 ","pages":"e70109"},"PeriodicalIF":2.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Potential of Lentiviral miR-200a Mimics in Regulating Fibrinolysis and EMT Markers During Pulmonary Fibrosis.","authors":"T M Jeena, C Rakshitha, Akarsha B Jain, Vaishnavi, Fathima Razana, Aleena Varughese, M Fathimath Muneesa, Yashodhar P Bhandary","doi":"10.1096/fba.2025-00276","DOIUrl":"10.1096/fba.2025-00276","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the excessive accumulation of collagen-rich extracellular matrix (ECM), leading to the replacement of normal lung architecture. This pathological remodeling is primarily caused by the epithelial-to-mesenchymal transition (EMT), in which epithelial cells lose their polarity and adhesion and acquire mesenchymal characteristics that encourage the deposition of ECM and the growth of fibrotic tissue. The disruption of ECM homeostasis caused by dysregulated MMP-2 and MMP-9 activity in IPF paradoxically promotes abnormal tissue remodeling and fibrosis. IPF's unknown etiology, delayed diagnosis, and lack of effective treatments point to a crucial knowledge gap regarding ECM- and EMT-driven fibrosis. The microRNA-200 (miR-200) family has been found to be important EMT regulators in recent research, suggesting that they may be able to influence the course of fibrosis. Hereby the current study provides an insight on the role of miR-200a in regulating MMP-2 and MMP-9 in bleomycin (BLM)-induced lung fibrosis using both in vitro (A549 cells) and in vivo (C57BL/6 mice) models. A549 cells were transfected with a synthetic miR-200a mimic, and MMP expression was analyzed using RT-qPCR. In vivo, mice were intranasally administered a lentiviral vector expressing miR-200a prior to BLM induction, followed by tissue analysis at days 14 and 21 using histological stains and immunofluorescence. Gene and protein expression were quantified via RT-qPCR and western blotting. Our findings indicate that miR-200a mitigates fibrosis by downregulating MMPs and PAI-1 while upregulating uPA and uPAR, suggesting a protective role of miR-200a and its potential as a therapeutic target for pulmonary fibrosis.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":"e70096"},"PeriodicalIF":2.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Hypoxia Reduces Adenylyl Cyclase 6 Expression and Function in Bronchial Epithelial Cells.","authors":"Ryan H Cunnington, Nisha Singh, Marziyeh Shafizadeh, John W Hanrahan, Shyamala Dakshinamurti, Prashen Chelikani","doi":"10.1096/fba.2025-00309","DOIUrl":"https://doi.org/10.1096/fba.2025-00309","url":null,"abstract":"<p><p>Hypoxia is associated with a range of maladies, inflammation, and impaired immunity. The airway epithelial barrier contends with constant exposure to microbes but can be weakened with hypoxia and diseases, such as cystic fibrosis (CF). People with CF (pwCF) have defective cystic fibrosis transmembrane conductance regulator (CFTR) function leading to reduced immune function, excess mucous accumulation, and chronic infection. CFTR is a cAMP-dependent anion channel that is regulated in part by adenylyl cyclase 6 (AC6). G protein-coupled receptors (GPCRs) such as the chemosensory bitter taste receptors (T2Rs) have been shown to alter inhibitory G proteins and cAMP levels. T2Rs also mediate innate immunity responses and detect quorum sensing molecules (QSMs) through T2R14. The impact of hypoxia on these processes, in human airways, has not yet been characterized. We analyzed protein expression and functional endpoints at normal (21%), mild (10%), and severe (1%) oxygen levels to establish the effects of hypoxia on these processes in human bronchial epithelial cells. Our results show that severe hypoxia leads to decreased AC6 expression without altering Gαi/Gαs/T2R14 compared to wild-type controls. Hypoxia induced ligand and oxygen dependent effects on T2R14 functional responses to fungal QSMs, farnesol, and tyrosol. IL-5 release was increased in QSM treated CF cells at 1% oxygen. Severe hypoxia inhibited forskolin-induced currents due to CFTR and reduced cAMP. These results demonstrate expression level and functional alterations due to hypoxia in airway epithelia, including evidence that reduced AC6 expression and function in severe hypoxia is associated with CFTR dysfunction, establishing a potential link between these proteins and the functional outcome of airway epithelial response to hypoxia.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":"e70102"},"PeriodicalIF":2.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A TLR8 Variant Identified From Whole Exome Sequencing as a Sepsis-Prone Mutation.","authors":"Fahd Alhamdan, Stefano Gianoli, Xioahui Han, Sophia Koutsogiannaki","doi":"10.1096/fba.2026-00049","DOIUrl":"https://doi.org/10.1096/fba.2026-00049","url":null,"abstract":"<p><p>Sepsis remains a leading cause of morbidity and mortality worldwide, with outcomes highly influenced by host immune responses. While environmental and pathogen-related factors are well recognized, the contribution of host genomic variants to sepsis susceptibility and severity is increasingly appreciated. Because approximately 85% of known disease-causing mutations reside in the exome, whole exome sequencing (WES) offers a powerful strategy to uncover pathogenic variants in critically ill patients and to identify potential inborn errors of immunity that may modulate disease course. In the present study, we performed WES on 31 sepsis patients across different age groups, stratified into pre-school-aged children, school-aged children, and adults, and identified multiple genes harboring high- or medium-impact variants. Of particular interest, a high-impact TLR8 variant (rs3764880: A>G; p.Met1Val) was observed across all the age groups and predominantly in individuals with bacterial sepsis. Single-cell RNA sequencing of peripheral blood mononuclear cells demonstrated that TLR8 was highly expressed in non-classical monocytes, with transcription levels markedly elevated in carriers of the variant. Functional studies revealed that this TLR8 variant enhanced IFN-β secretion upon ligand stimulation, suggesting that dysregulated TLR8 signaling might modulate host inflammatory responses during bacterial sepsis. Given the established role of IFN-β in exacerbating sepsis severity, these findings support a model in which the TLR8 rs3764880 variant contributes to sepsis pathophysiology by amplifying IFN-β-mediated monocyte responses. This study underscores the importance of integrating genomic and functional immunologic analyses to identify host determinants of sepsis, highlights TLR8 as a potential biomarker and therapeutic target, and provides a framework for precision medicine approaches to predict and modulate outcomes in bacterial sepsis.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":"e70106"},"PeriodicalIF":2.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13080694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transamniotic Fetal Delivery of Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR) mRNA","authors":"Kamila Moskowitzova,&nbsp;Ashlyn E. Whitlock,&nbsp;Yash V. Shroff,&nbsp;David Zurakowski,&nbsp;Dario O. Fauza","doi":"10.1096/fba.2025-00288","DOIUrl":"10.1096/fba.2025-00288","url":null,"abstract":"<p>We sought to determine whether a cystic fibrosis transmembrane conductance regulator (CFTR) mRNA could be administered to the fetus via the transamniotic route as a potential strategy for the perinatal management of cystic fibrosis-associated meconium ileus. Nine pregnant Sprague Dawley dams underwent volume-matched intra-amniotic injections in all their fetuses (<i>n</i> = 109) of either a suspension of a human CFTR mRNA encapsulated by a semi-synthetic composite, lipopolyplex (mRNA group; <i>n</i> = 98), or of a suspension of the same composite free of mRNA (control group; <i>n</i> = 11), on gestational day 17 (E17; term = E21). At daily time points until term, fetal small bowel and lungs, along with maternal serum, were quantitatively screened for the human CFTR protein by ELISA. Statistical analysis was by the nonparametric Wilcoxon rank sum test with Bonferroni adjustment. Overall fetal survival was 85.3% (93/109), with no significant differences between the groups or time points. When controlled by mRNA-free injections, human CFTR was detected in the small bowel from the mRNA group at all time points (<i>p</i> &lt; 0.001 for all), increasing initially over time. Human CFTR was detected comparably in the lungs from both groups, suggesting interspecies homology at that anatomical site. No human CFTR was detected in maternal serum. Encapsulated exogenous mRNA encoding for the cystic fibrosis transmembrane conductance regulator protein can be incorporated and translated by fetal small bowel cells after simple intra-amniotic injection in a healthy rodent model. Transamniotic mRNA delivery could become a novel strategy for the perinatal management of meconium ileus associated with cystic fibrosis.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13058431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}