FASEB Journal[JOURNAL]
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200 papers
Time- and Region-Specific Effects of Intranasal Insulin on Oxidative Stress Parameters in the Rat Brain.
Osmanovic Barilar J, Vlahov L, Krsnik A … +6 more , Mihalic L, Babic Perhoc A, Virag D, Homolak J, Salkovic-Petrisic M, Knezovic A
FASEB J · 2026 Jul · PMID 42402181 · Publisher ↗
Understanding how intranasal insulin affects brain signaling and metabolism is essential for elucidating its therapeutic potential in neurodegenerative disorders with underlying metabolic dysfunction, such as Alzheimer's...
Understanding how intranasal insulin affects brain signaling and metabolism is essential for elucidating its therapeutic potential in neurodegenerative disorders with underlying metabolic dysfunction, such as Alzheimer's disease (AD). Oxidative stress, which increases with aging, has been observed in both AD and Type 2 diabetes, indicating a potential link between oxidative stress, brain insulin resistance and cognitive impairment. This study examined how intranasal insulin affects redox homeostasis across different brain regions and time points. Male Wistar rats received 2 IU of insulin intranasally and were sacrificed 3, 7.5, 15, 30, 60, and 120 min post-administration. Six animals served as intact controls. Redox homeostasis was assessed by measuring lipid peroxidation, total reductive capacity, thiol concentrations, and superoxide dismutase activity in plasma, nasal epithelia, and brain regions. The results were correlated with insulin signaling markers. Intranasal insulin induced rapid but regionally diverse redox responses. The most pronounced alterations occurred in nasal epithelia, where respiratory and olfactory regions exhibited distinct and opposing patterns. In the brain, significant alterations, particularly in thiol-related parameters, were observed across multiple regions including cortices, hippocampus, hypothalamus, olfactory bulb, and cerebellum. Plasma redox parameters remained largely unchanged, supporting the predominantly central action of intranasally delivered insulin. Correlation analyses revealed associations between oxidative stress markers and insulin signaling parameters, suggesting complex interactions between metabolic signaling pathways and redox regulation. These findings demonstrate that intranasal insulin modulates redox homeostasis in a rapid, region-specific, and time-dependent manner, highlighting the importance of spatial and temporal factors in insulin-mediated regulation of brain oxidative balance.
Brown Adipose Tissue Secreted Nrg4 Prevents Bone Loss by Orchestrates Bone Resorption and Angiogenesis.
Xu X, Zhou J, Tang M … +3 more , Zhang Y, Hu J, Shi L
FASEB J · 2026 Jul · PMID 42402178 · Publisher ↗
Beyond established roles in metabolic regulation, adipose tissue-derived factors are increasingly recognized as critical modulators of bone mass. Nevertheless, the underlying mechanisms that coordinate the osteoclastogen...
Beyond established roles in metabolic regulation, adipose tissue-derived factors are increasingly recognized as critical modulators of bone mass. Nevertheless, the underlying mechanisms that coordinate the osteoclastogenesis-angiogenesis-osteogenesis axis to maintain skeletal homeostasis remain poorly defined. Mouse models including brown adipose tissue (BAT) removal, Neuregulin 4 (Nrg4) knockout (Nrg4), and BAT transplantation were used to evaluate the role of BAT-secreted Nrg4 in bone homeostasis. In vitro experiments were performed to explore the effects of Nrg4 on osteoclastogenesis and the angiogenesis-osteogenesis coupling. Additionally, exogenous Nrg4 treatment was applied to ovariectomy (OVX)-induced osteoporotic mice to assess its therapeutic potential. BAT removal or Nrg4 knockout resulted in increased bone resorption and decreased bone formation, thereby accelerating bone loss in mice; conversely, BAT transplantation rescued the skeletal phenotype of Nrg4 mice. In vitro, Nrg4 significantly inhibited osteoclastogenesis, at least partially through the NF-κB inflammatory signaling pathway, while simultaneously activating the angiogenesis-osteogenesis coupling via PDGF-BB derived from preosteoclasts. Furthermore, exogenous Nrg4 treatment effectively attenuated bone loss in OVX-induced osteoporotic mice. These findings demonstrate that BAT-derived Nrg4 acts as a key regulator of bone homeostasis and represents a promising therapeutic target for bone loss disorders by orchestrating crosstalk between osteoclasts and endothelial cells.
Shared Genetic Risk Between Acute Pancreatitis and Metabolic Syndrome Converges on a BCAT1-Positive Fibroblast Subpopulation and MAPK14-Driven Inflammation.
Zhou X, Yang C, Zou T … +4 more , Basharat Z, Zippi M, Fiorino S, Hong W
FASEB J · 2026 Jul · PMID 42402174 · Publisher ↗
Metabolic syndrome (MetS) has been associated with increased acute pancreatitis (AP) severity. This study aimed to identify shared differentially expressed genes (CDEGs) between MetS and AP and to prioritize mechanistica...
Metabolic syndrome (MetS) has been associated with increased acute pancreatitis (AP) severity. This study aimed to identify shared differentially expressed genes (CDEGs) between MetS and AP and to prioritize mechanistically relevant targets. The shared genetic basis and causal effect of MetS on AP were first assessed using linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomization (MR). Public Gene Expression Omnibus (GEO) datasets were analyzed to define shared CDEGs. A multi-step pipeline incorporating functional enrichment, protein-protein interaction (PPI) analysis, and transcription factor mapping was used to identify AP hub genes (AP-HGs). Functional relatedness and putative causal relationships were evaluated using GeneMANIA, MR, and single-cell RNA sequencing (scRNA-seq). Finally, computational drug prediction and molecular docking were performed to identify potential therapeutic agents. Key findings were further validated in a hyperlipidemia AP (HAP) model. A positive genetic correlation between MetS and AP was identified by LDSC, and MR supported a causal effect of MetS on increased AP risk. BCAT1, GPAT3, ANP32C, and ZNF683 were identified as CDEGs between MetS and AP. MAPK14 was identified as a central AP-HG. MAPK14, BCAT1, and GPAT3 were effective predictors for severe AP (SAP), with AUCs of 0.738, 0.722, and 0.744, respectively. GeneMANIA predicted a high degree of physical interaction (77.6%) among these genes. MR analysis provided supportive genetic evidence linking MAPK14 expression to inflammatory mediators including IL-1ra and TNFR-1. scRNA-seq analysis in an experimental AP model localized Mapk14 expression predominantly to macrophages, while Bcat1 marked a unique, proliferative fibroblast subpopulation that emerged transiently during inflammation and exhibited an anabolic metabolic signature. Ozagrel was prioritized as an exploratory candidate with favorable predicted binding affinities and requires further validation. In a HAP model, aggravated pancreatic injury and upregulation of BCAT1 and MAPK14 were confirmed under the high-fat background. A genetic and transcriptomic link between MetS and AP was identified. MAPK14-associated inflammation and Bcat1-positive fibroblast remodeling may contribute to AP aggravation under metabolic disturbance. These findings provide candidate biomarkers for SAP prediction and support BCAT1 and MAPK14 as potential mechanistic targets.
IL-33/ST2 Signaling Sustains Hepato-Intestinal Homeostasis by Orchestrating Vascular Surveillance and Immune Regulatory Circuits During Experimental Trypanosoma cruzi Infection.
Cardozo ME, Cirilo TM, da Rocha Rihs JB … +20 more , Souza JLN, de Brito Duval I, Antunes-Porto AR, do Amaral LVB, Oliveira FBR, Ricci MF, de Oliveira Santos LL, Santana LFD, Silva LP, Amorim CCO, Lemos GGM, Junior GMES, da Silva Oliveira I, Dos Reys MP, de Oliveira ALG, Cassali GD, Magalhães LMD, Bueno LL, Machado FS, Fujiwara RT
FASEB J · 2026 Jul · PMID 42402170 · Publisher ↗
Chagas disease, caused by Trypanosoma cruzi, is characterized by a complex interplay between parasite persistence and host-driven immunopathology. Although the IL-33/ST2 axis is known to regulate type 2 immunity and tiss...
Chagas disease, caused by Trypanosoma cruzi, is characterized by a complex interplay between parasite persistence and host-driven immunopathology. Although the IL-33/ST2 axis is known to regulate type 2 immunity and tissue repair, its contribution to tissue homeostasis during chronic infection remains poorly understood. Using ST2-deficient (ST2) and wild-type BALB/c mice followed for up to 100 days postinfection, we investigated the role of IL-33/ST2 signaling in coordinating hepato-intestinal response and systemic immunity. ST2 deficiency induced coordinated systemic disturbances, including platelet expansion and hyperalbuminemia. At the tissue level, loss of ST2 exacerbated hepatic inflammation and fibrotic remodeling. In the colon, ST2 mice displayed increased nitric oxide production and enhanced parasite clearance, but developed marked structural alterations. Our findings suggest that IL-33/ST2 signaling is associated with regulatory programs. ST2 deficiency was associated with a reduction in patrolling monocytes, suggesting impaired homeostatic endothelial monitoring. This profile also coincided with inflammatory monocyte-derived dendritic cell differentiation and lowered macrophage regulatory activity. This altered profile was associated with amplified IL-12-driven Th1 and cytotoxic T-cell responses while impairing IL-10-associated regulatory niches, resulting in multiorgan inflammation. These findings suggest that IL-33/ST2 signaling may contribute to immunoregulatory balance during T. cruzi infection and identify this axis as a candidate pathway for future mechanistic and therapeutic investigation.
Adipocyte-Derived Exosomal Circ_0000002 Affects the Myoblast Growth and Muscle Regeneration.
Liang L, Zhang W, Yu S … +4 more , Chen H, Yan J, Huo J, Zhao J
FASEB J · 2026 Jul · PMID 42402163 · Publisher ↗
Skeletal muscle development is strongly influenced by crosstalk between adipose tissue and muscle, yet the underlying molecular mechanisms in Ovis aries remain insufficiently defined. This study investigated the regulato...
Skeletal muscle development is strongly influenced by crosstalk between adipose tissue and muscle, yet the underlying molecular mechanisms in Ovis aries remain insufficiently defined. This study investigated the regulatory effects of adipocyte-derived exosomes on sheep primary myoblasts. Co-culture with adipocytes significantly enhanced myoblast proliferation, as indicated by increased cyclin-dependent kinase 4 (CDK4), proliferating cell nuclear antigen (PCNA), and Cyclin D1 expression, while simultaneously suppressing differentiation via reduced myogenin (MYOG), myogenic differentiation 1 (MYOD), and myosin heavy chain (MYHC) levels. Exosomes isolated from mature adipocytes (30-150 nm), expressing TSG101, CD63, and CD9, were effectively internalized by myoblasts and reproduced these effects. RNA sequencing identified circ_0000002 as one of the most abundant circular RNAs (circRNAs) in adipocyte-derived exosomes. Functional assays demonstrated that circ_0000002 promoted myoblast proliferation and inhibited differentiation. Mechanistically, circ_0000002 acted as a competing endogenous RNA (ceRNA) by sponging miR-27a, thereby relieving miR-27a-mediated repression of myostatin (MSTN). Dual-luciferase reporter assays confirmed direct interactions between circ_0000002 and miR-27a and between miR-27a and the MSTN 3' untranslated region (3´UTR). Co-transfection experiments further validated that the ceRNA-like mechanism of circ_0000002/miR-27a/MSTN regulates myoblast differentiation. In a cardiotoxin (CTX)-induced tibialis anterior injury mouse model, intramuscular administration of adipocyte-derived exosomes impaired muscle regeneration and increased MSTN expression, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that exosomal circ_0000002 regulates sheep myoblast differentiation via miR-27a/MSTN ceRNA pathway. This work provides the first evidence that an adipocyte-derived exosomal circRNA mediates fat-muscle communication and highlights a potential target for improving muscle growth in sheep.
Sinomenine Regulates the TRIM32/IRF1/TRAF6 Axis to Inhibit Pyroptosis in Atopic Dermatitis.
Xia J, Liu Y, Bai Q … +5 more , Gong K, Liu Y, Tan Z, Luo J, Zhu M
FASEB J · 2026 Jul · PMID 42394466 · Publisher ↗
Atopic dermatitis (AD) is a persistent skin disorder involving inflammation and marked by immune dysregulation. Sinomenine, a plant-derived alkaloid with known anti-inflammatory properties, remains underexplored regardin...
Atopic dermatitis (AD) is a persistent skin disorder involving inflammation and marked by immune dysregulation. Sinomenine, a plant-derived alkaloid with known anti-inflammatory properties, remains underexplored regarding its role in pyroptosis associated with AD. An in vitro AD-like model was established using HaCaT cells stimulated with IFN-γ (10 ng/mL) and TNF-α (10 ng/mL). Sinomenine pretreatment was evaluated for its ability to attenuate inflammation, pyroptosis, and cell damage using ELISA, MTT, LDH assays, flow cytometry, and Western blot. The underlying mechanism was explored via ChIP-qPCR, luciferase assays, and protein interaction studies including co-immunoprecipitation and immunofluorescence. IFN-γ/TNF-α triggered robust pyroptosis in HaCaT cells, characterized by elevated IL-18, IL-6, IL-8, IL-1β, and increased NLRP3 expression levels, cleaved Caspase-1, and GSDMD-N. Sinomenine pretreatment significantly reversed these effects, improving cell viability and reducing inflammatory cytokine production and pyroptosis markers. Mechanistically, sinomenine downregulated TRAF6 expression, a known activator of the NLRP3 inflammasome, by inhibiting its transcriptional regulator IRF1. IRF1 directly bound the TRAF6 promoter and promoted its transcription. Furthermore, sinomenine enhanced TRIM32 expression, which promoted the ubiquitination and proteasomal degradation of IRF1, thus interrupting the IRF1/TRAF6/NLRP3 axis. Sinomenine protects HaCaT cells from IFN-γ/TNF-α-induced pyroptosis by promoting TRIM32-mediated degradation of IRF1, leading to downregulation of TRAF6 and subsequent attenuation of the NLRP3 inflammasome activation. These findings highlight the therapeutic potential of sinomenine for inflammatory skin diseases like AD.
Urolithin A Mitigates Renal Fibrosis by Promoting Fatty Acid Oxidation Through Orchestrating β-Catenin Signaling.
Li Y, Wei J, Li J … +1 more , Zhu W
FASEB J · 2026 Jul · PMID 42394439 · Publisher ↗
Kidney fibrosis, a progressive outcome of various chronic kidney diseases (CKD), features tubule atrophy, chronic interstitial inflammation, and abnormal metabolic changes. Urolithin A (UA), a gut microbiome metabolite d...
Kidney fibrosis, a progressive outcome of various chronic kidney diseases (CKD), features tubule atrophy, chronic interstitial inflammation, and abnormal metabolic changes. Urolithin A (UA), a gut microbiome metabolite derived from ellagic acid and ellagitannins, has anti-inflammatory and anti-obesity effects and enhances cellular health by promoting mitophagy and mitochondrial function. This study aimed to evaluate the protective effects of UA against renal fibrosis in mice with unilateral ureteral obstruction (UUO) and to investigate its underlying mechanisms. UA significantly reduced lipid deposition and mitigated renal fibrosis in the kidneys of UUO mice and TGFβ1-induced HK-2 cells. Mechanistically, UA alleviated renal fibrosis by inhibiting GSK3β/β-catenin signaling to promote FAO, rather than through the canonical TGF-β1/Smad or Notch1 signaling pathways. Furthermore, UA activates GSK3β to inhibit β-catenin via AKT1 but independent of SIRT3 or PP2A. Altogether, UA significantly mitigated kidney fibrosis by restoring fatty acid oxidation metabolism through inactivation of the GSK3β/β-catenin axis, offering potential as an alternative therapy to combat renal fibrosis.
MiR-124 Inhibits Lipid Deposition in Mouse Liver by Targeting the Trib3/Hnf4α Pathway.
Wang X, Zhao Y, Yao Y … +6 more , Li M, Jing L, Wang K, Zhang L, Chen J, Wei W
FASEB J · 2026 Jul · PMID 42394428 · Publisher ↗
Non-alcoholic fatty liver disease (NAFLD) arises from dysregulated lipid homeostasis, encompassing imbalances in lipid uptake, synthesis, and catabolism in liver. Despite its global prevalence and clinical impact, effect...
Non-alcoholic fatty liver disease (NAFLD) arises from dysregulated lipid homeostasis, encompassing imbalances in lipid uptake, synthesis, and catabolism in liver. Despite its global prevalence and clinical impact, effective therapeutic strategies for NAFLD remain elusive. A previous study showed that miR-124 inhibits adipogenic differentiation of murine 3T3-L1 cells by targeting the glucocorticoid receptor (GR). Furthermore, the liver-to-body weight ratio and plasma cholesterol levels were significantly elevated in miR-124 promoter KO mice compared to wildtype controls. Therefore, this study aims to investigate the role of miR-124 in hepatic lipid metabolism and its potential regulatory mechanism. We demonstrate that miR-124 expression is downregulated in hepatocyte lipid deposition model, and its overexpression suppresses lipid deposition by downregulating fatty acid uptake/synthesis genes (e.g., Cd36, Fasn) and upregulating fatty acid β-oxidation/lipolysis/VLDL secretion genes (e.g., Pparα, Cpt-1, Atgl, Apob). Conversely, miR-124 inhibition exacerbates steatosis in vitro. Mechanistically, Tribbles homolog 3 (Trib3) is identified as a direct target of miR-124, and miR-124 negatively regulates Trib3 expression to upregulate hepatocyte nuclear factor 4α (Hnf4α), a liver-specific transcription factor critical for lipid homeostasis. MiR-124 promoter knockout mice confirm that miR-124 deficiency elevates hepatic Trib3, reduces Hnf4α, and promotes lipid accumulation. Collectively, our findings identify the miR-124/Trib3/Hnf4α axis as a novel regulatory pathway in hepatic lipid metabolism, highlighting its potential as a therapeutic target for NAFLD.
TCN2 Drives Psoriasis-Like Inflammation and Keratinocyte Hyperproliferation, Correlating With IL-1β and STAT3 Activation.
Xu JK, Zhou XZ, Xue K … +6 more , Li A, Xia QY, Zhuang Z, Song XJ, Zuo XB, Cui Y
FASEB J · 2026 Jul · PMID 42394410 · Publisher ↗
Psoriasis is a chronic immune-mediated inflammatory disorder with systemic implications. While transcobalamin 2 (TCN2) has been linked to several autoimmune diseases, its role in psoriasis remains unclear. Here, we inves...
Psoriasis is a chronic immune-mediated inflammatory disorder with systemic implications. While transcobalamin 2 (TCN2) has been linked to several autoimmune diseases, its role in psoriasis remains unclear. Here, we investigated the contribution of TCN2 to psoriatic pathogenesis. TCN2 expression was significantly elevated in both lesional skin and peripheral blood mononuclear cells (PBMCs) from psoriasis patients, and its levels declined following biologic therapy. Similarly, increased TCN2 expression was observed in imiquimod (IMQ)-induced psoriatic lesions in mice. To further evaluate its function, we generated Tcn2-deficient (Tcn2-/-) mice and established an IMQ-induced psoriasis model. Compared with wild-type controls, Tcn2-/- mice developed attenuated skin lesions with reduced epidermal hyperplasia and inflammation. Transcriptomic analysis of lesional skin revealed downregulation of inflammatory mediators (S100A7, S100A8, S100A9, IL-1β, IL-6) and suppression of STAT3 signaling in Tcn2-/- mice. In parallel, TCN2-knockdown HaCaT cells exhibited impaired proliferation due to G1-phase arrest, along with reduced expression of proinflammatory factors. Together, these findings demonstrate that TCN2 promotes keratinocyte hyperproliferation and amplifies inflammatory responses in psoriasis. In conclusion, this study identifies TCN2 as a previously unrecognized regulator of psoriatic inflammation and keratinocyte biology, highlighting its potential as a novel therapeutic target.
The Synthetic Melanocortin Agonist NDP-MSH Ameliorates THSD7A-Associated Membranous Nephropathy in an Active Immunization Mouse Model.
Zhang M, Chen M, Ge Y … +2 more , Gunning W, Gong R
FASEB J · 2026 Jul · PMID 42394403 · Full text
Melanocortin-based therapies have demonstrated protective effects in experimental membranous nephropathy (MN). However, existing evidence is derived exclusively from passive immunization models that lack direct involveme...
Melanocortin-based therapies have demonstrated protective effects in experimental membranous nephropathy (MN). However, existing evidence is derived exclusively from passive immunization models that lack direct involvement of human MN-associated autoimmunity, limiting translational relevance. A clinically relevant model is essential to more precisely define melanocortin efficacy and mechanisms in MN. To address this gap, we established an active immunization model of THSD7A-associated MN by immunizing mice with recombinant THSD7A antigen. This clinically relevant and accessible model recapitulated cardinal features of human MN, including insidious onset, progressive proteinuria, and characteristic histopathology such as subepithelial immune deposition, complement fixation along glomerular tufts, glomerular basement membrane thickening, and podocyte injury with foot process effacement and loss of homeostatic markers. Rescue treatment with the pan-melanocortin receptor agonist NDP-MSH significantly reduced proteinuria and mitigated glomerular damage and podocyte injury. This was accompanied by a marked reduction in circulating anti-THSD7A autoantibody levels, reduced glomerular immune deposition, and diminished complement activation. Mechanistically, ex vivo treatment of primed B cells isolated from diseased mice demonstrated that NDP-MSH directly inhibited plasma cell differentiation and autoantibody production. This suppression was accompanied by increased expression of microphthalmia-associated transcription factor (MITF) and downregulation of interferon regulatory factor 4 (IRF4), indicating activation of the MITF/IRF4 signaling axis, a pathway implicated in negative regulation of B cell differentiation. Collectively, these findings extend the therapeutic potential of melanocortin signaling to a preclinical model that closely mirrors human MN and provide mechanistic insight into its immunomodulatory actions. These results support further investigation of targeted melanocortin-based therapies for MN.
Brain-Derived Neurotrophic Factor and Associated Signaling in Kidney Diseases.
Xue C, Wei Q, Wang S … +4 more , Byers A, Huang J, Chen JK, Dong Z
FASEB J · 2026 Jul · PMID 42394379 · Publisher ↗
Brain-derived neurotrophic factor (BDNF) is a key member of the neurotrophin family that promotes neuronal function via its receptor kinase TrkB. However, recent work has demonstrated BDNF as a multifaceted regulator bey...
Brain-derived neurotrophic factor (BDNF) is a key member of the neurotrophin family that promotes neuronal function via its receptor kinase TrkB. However, recent work has demonstrated BDNF as a multifaceted regulator beyond its classic roles in the nervous system, particularly in renal patho-physiology. This review summarizes the recent advances about BDNF/TrkB signaling pathway in various kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI). Upon binding TrkB, BDNF initiates specific intracellular signaling pathways, such as PI3K-Akt, MAPK-ERK, and PLCγ, to support cell survival, mitochondrial function, cytoskeletal integrity, and anti-inflammatory responses. As such, the BDNF-TrkB pathway represents a potential target for renal protection and regeneration, warranting further mechanistic and clinical investigation.
The Role of Meprins on the Brain Extracellular Matrix and Perineuronal Nets.
Kreiselmaier S, Keller M, Nardi L … +11 more , Mueller C, von Wiegen N, Bickenbach K, Gröbner L, Abukhalaf M, Tholey A, Mueller MM, Körschgen H, Schmeisser MJ, Becker-Pauly C, Pietrzik CU
FASEB J · 2026 Jul · PMID 42394367 · Full text
Meprin α and meprin β are zinc metalloproteases that are strongly expressed in intestinal and renal tissues and are expressed as homo- and heterodimers. In the kidney and intestine, they are involved in extracellular mat...
Meprin α and meprin β are zinc metalloproteases that are strongly expressed in intestinal and renal tissues and are expressed as homo- and heterodimers. In the kidney and intestine, they are involved in extracellular matrix assembly and modulation of inflammatory responses. However, meprin β has recently attracted attention because it generates Alzheimer's Disease (AD)-specific Aβ peptides and cleaves brevican, a major component of the perineuronal nets (PNNs) in the brain. PNNs stabilize synapses, thereby regulating plasticity and memory formation. Brevican cleavage correlated with impaired spatial memory formation and impaired CA1 long-term potentiation (LTP) in meprin β transgenic mice. Furthermore, numerous studies have shown the dysregulation of PNN components in AD. Still, the physiological and pathological functions of proteolytic PNN remodeling remain elusive. This study identified an essential role of meprin α in brevican cleavage. It enhanced meprin β's catalytic activity on brevican in co-expression. Moreover, an N-terminomics analysis identified novel meprin β substrates, neurocan, and receptor-type tyrosine-protein phosphatase zeta (RPTPζ) in the brain. Both are key components of PNNs. RPTPζ cleavage by meprin α and meprin β was confirmed in vitro. To assess the functional impact of meprin-mediated proteolysis on the brain extracellular matrix, PNNs and synaptic organization were investigated in vivo using immunofluorescence and electron microscopy. Meprin-mediated proteolysis disrupted PNN structure and decreased synapse density in the hippocampal CA1 region of meprin β transgenic mice. This identifies meprin-dependent PNN remodeling as a novel mechanism contributing to synaptic dysfunction.
FGFR Inhibitor AZD4547 Disrupts Inflammatory CAF Crosstalk With Cancer Cells and Macrophages and Attenuates Metastasis in Pancreatic Cancer.
Mostafa AMRH, Hemdan AG, Assayag F … +1 more , Prakash J
FASEB J · 2026 Jul · PMID 42394340 · Full text
Cancer-associated fibroblasts (CAFs) are key cell types within the tumor microenvironment (TME), responsible for their pro-tumorigenic effects and metastasis. Specifically, inflammatory CAFs (iCAFs), a CAF subtype, are k...
Cancer-associated fibroblasts (CAFs) are key cell types within the tumor microenvironment (TME), responsible for their pro-tumorigenic effects and metastasis. Specifically, inflammatory CAFs (iCAFs), a CAF subtype, are known to induce tumor cell progression, migration, and immunosuppression. Fibroblast growth factor receptors (FGFRs) play a crucial role in cell differentiation, migration, and proliferation. In this study, we investigated the effect of FGFR kinase inhibitor AZD4547 (AZD), a clinical-stage drug, on iCAF differentiation and iCAF-mediated effects on the tumor-stroma interaction in vitro and in vivo. Treatment with AZD inhibited the differentiation of human pancreatic stellate cells into iCAFs using IL-1α, as shown with reduced IL-6 expression. FGFR1, 2, 3, and 4 were upregulated in iCAFs, which were inhibited by AZD. Treatment with AZD also attenuated the iCAF-mediated paracrine effect on the PDAC cell-induced migration and epithelial-mesenchymal transition of tumor cells, as well as polarization of macrophages towards the M1 phenotype in vitro. Furthermore, AZD significantly reduced the growth of tumor cells and fibroblasts in co-cultured 3D heterospheroids in vitro. In vivo, treatment with AZD attenuated the tumor growth in the syngeneic subcutaneous KPC murine tumor model. Interestingly, flow cytometry and immunofluorescent staining analyses on isolated tumors revealed that AZD-treated tumors had a reduced iCAF population and M2-type macrophages. Furthermore, we found that AZD treatment reduced the liver metastasis, as shown with the reduction of ki-67 and p53 tumor markers in the AZD-treated group compared to the vehicle group. Altogether, this study demonstrates that FGFRs are overexpressed on iCAFs and their inhibition using AZD diminishes iCAF-mediated paracrine signaling with tumor cells and macrophages, thereby attenuating tumor growth and metastasis.
Utilizing Single-Cell and Transcriptomic Data to Identify Mitochondrial Pathway-Associated Prognostic Genes and Their Regulatory Mechanisms of Action in Ovarian Cancer.
Ruan Y, Liu X, Lin X … +3 more , Li Y, Yang Y, Lin F
FASEB J · 2026 Jul · PMID 42387880 · Publisher ↗
Mitochondrial abnormalities correlate closely with multiple cancers, but the role of genes associated with mitochondrial pathways in ovarian cancer (OC) remains unclear. This study aimed to identify OC prognosis-related...
Mitochondrial abnormalities correlate closely with multiple cancers, but the role of genes associated with mitochondrial pathways in ovarian cancer (OC) remains unclear. This study aimed to identify OC prognosis-related mitochondrial pathway-associated genes at single-cell and transcriptome levels. Public datasets (GSE184880, GSE54388, GSE18520, TCGA-OV) were retrieved. Using GSE184880, potential cell subpopulations and their tumor-control differentially expressed genes (DEGs) were identified, then intersected with GSE54388 key module genes to yield candidate genes. Univariate Cox regression and LASSO analyses were performed to screen prognostic genes, based on which a prognostic risk model was constructed and validated. Functional and localization analyses of prognostic genes, regulatory network construction, immune infiltration analysis, drug prediction, and expression verification were conducted. Pseudotime, cell communication and expression analyses were implemented at single-cell level. To account for patient-level variation, mixed-effects models using the MAST method were applied. Targeted GSEA focusing on mitochondrial functional pathways was performed. Clinical correlation, independent prognostic analysis, and computational functional inference were conducted. Eight cell types were observed by cell clustering and annotation, among which endothelial cells, fibroblasts, NK cells, and tissue stem cells were observed as potential cell subpopulations. TK1, VWF, CPXM1, WIPF3, APOLD1, MGST2, and PPA1 were identified as prognostic genes, and risk models constructed based on them had good performance and universality. Mixed-effects model analysis confirmed that 1200 DEGs remained significant after adjusting for patient-level variation, supporting the robustness of single-cell findings. These prognostic genes were found to be robust predictors of patient survival with inconsistent expression patterns in vitro, and may play important roles in the differentiation and development of key cells. Targeted GSEA revealed that mitochondrial respiration (electron transport chain/oxidative phosphorylation) and mitophagy were significantly suppressed in the high-risk group, while mitochondrial fusion/fission and ROS pathways did not reach significance. PPA1 was highly expressed in various cell types in the GSE184880 dataset. In the GSE54388 dataset, CPXM1 and WIPF3 were substantially downregulated in the tumor group. However, other prognostic genes displayed the opposite expression pattern. Single-cell functional inference showed that TK1 and APOLD1 were highly expressed in G2/M phase, while MGST2, PPA1, VWF, CPXM1, and WIPF3 were enriched in G1 phase. VWF showed the strongest positive correlation with the PI3K-AKT pathway. Clinical validation confirmed the independent prognostic value of the signature in advanced-stage OC (FIGO III/IV). Seven mitochondrial pathway-associated prognostic genes were identified in OC, with inconsistent survival and in vitro expression patterns, providing novel references for exploring potential therapeutic targets.
Gene-Environment Interactions in Childhood Asthma: From Prenatal Exposures to Targeted Interventions.
Li S, Shang W, Luo H … +4 more , Sun B, Li Y, Meng F, Gao M
FASEB J · 2026 Jul · PMID 42384431 · Publisher ↗
Asthma is one of the most common chronic respiratory diseases affecting both children and adults worldwide. Its pathogenesis is driven by complex interactions between genetic susceptibility and environmental exposures. I...
Asthma is one of the most common chronic respiratory diseases affecting both children and adults worldwide. Its pathogenesis is driven by complex interactions between genetic susceptibility and environmental exposures. Investigating gene-environment (G × E) interactions holds significant potential to elucidate the regulatory genetic architecture underlying individual responses to environmental risk factors in childhood asthma. In this review, we systematically summarize the environmental exposure factors during prenatal and postnatal periods and analyze their independent effects on the risk of childhood asthma. Secondly, we explore the role of G × E interactions in asthma from three perspectives: statistical interaction, mechanistic interaction, and epigenetic-mediated interaction. Finally, we evaluate current treatment and intervention strategies, distinguish established recommendations for the general population from emerging and exploratory methods, and point out existing limitations. Our analysis reinforces that investigating G × E interactions is a robust approach for uncovering the molecular mechanisms underlying childhood asthma. Despite substantial technical challenges and unresolved questions regarding generalizability and heterogeneity, such investigative strategies are expected to enhance our understanding of asthma endotypes and the development of more effective, precision-based preventive and therapeutic interventions.
m6A-Modified KLF11 Inhibits Macrophage Foam Cell Formation by Transcriptionally Suppressing ATP5B Expression in Atherosclerosis.
Yang X, Gu Z, Chen C … +3 more , Si L, Mei H, Gu W
FASEB J · 2026 Jul · PMID 42384007 · Publisher ↗
Macrophage foam cell formation is the mark of atherosclerosis (AS). Krüppel-like factor (KLF)11 prevented the development of AS in diabetic conditions. However, it is not clear whether KLF11 inhibits macrophage foam cell...
Macrophage foam cell formation is the mark of atherosclerosis (AS). Krüppel-like factor (KLF)11 prevented the development of AS in diabetic conditions. However, it is not clear whether KLF11 inhibits macrophage foam cell formation. High-fat diet (HFD) was administered to ApoE mice to build an in vivo AS model. An adeno-associated virus (AAV) vector incorporating the macrophage-specific promoter CD68 was utilized to construct the macrophage-specific KLF11 overexpression mouse model. Treatment of RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) elicited foam cell formation. Dual luciferase reporter gene assays, ChIP, and RIP were applied to detect interactions between molecules. Pathological changes in arterial tissue were detected by HE staining, and the area of collagenous fibers was measured by Masson staining. Cholesterol efflux and cholesterol uptake were analyzed using NBD-cholesterol and Dil-ox-LDL methods, respectively. Lipid and inflammation levels were assessed using commercially available kits. Adipogenesis was assayed via Oil red O staining. KLF11 expression was downregulated, and overexpression of KLF11 suppressed inflammation, cholesterol levels, and lipid accumulation in AS. Meanwhile, overexpression of KLF11 inhibited ox-LDL-induced foam cell formation. Mechanistically, IGF2BP3 promoted KLF11 stabilization and expression in an m6A-dependent manner, and KLF11 transcriptionally inhibited ATP5B, which prevented NLRP3 inflammasome activation. IGF2BP3 mediated KLF11 stabilization to inhibit macrophage foam cell formation and alleviate AS through transcriptional inhibition of ATP5B to block NLRP3 inflammasome activation.
Dissecting Allele-Specific Expression (ASE) in Landrace × Meishan Cross Pig Fetal-Placental Tissues: Distribution, Functional Split, and Mechanisms.
Zhang J, Xu S, Wu W … +6 more , Zhang L, Jiang A, Shen M, Tao J, Liu H, Pan Z
FASEB J · 2026 Jul · PMID 42384001 · Publisher ↗
Allele-specific expression (ASE) is a key regulatory mechanism linking genetic variation to phenotypic diversity. This study conducted a genome-wide ASE analysis in embryonic (brain, kidney, liver) and extraembryonic (ch...
Allele-specific expression (ASE) is a key regulatory mechanism linking genetic variation to phenotypic diversity. This study conducted a genome-wide ASE analysis in embryonic (brain, kidney, liver) and extraembryonic (chorion) tissues of Landrace × Meishan crossbred pigs. By integrating DNA sequencing of parental and F1 hybrids and RNA-sequencing of F1 tissues, a high-resolution ASE landscape was built via strict allele-specific SNP identification. Genomically, ASE genes (ASEG) were enriched on chromosomes 6, 7, 12, X and sparse on chromosome 11, and can be classified into extreme/moderate types by expression pattern and parental bias. Paternal ASEGs had higher expression levels, while maternal ones had higher abundance. Functionally, tissue-concordant ASEGs supported embryo/placenta basal development, tissue-specific ones matched organ core functions; maternal ASEGs were enriched in mitochondrial pathways, paternal ones in cell motility and RNA transcription. Besides, chorion had more allele-specific methylated regions than embryonic tissues, with opposite ASE directions. We proposed "orthogonal dual regulatory dimensions" for the relationship between ASE and tissue-specific expression. We also proposed regulatory models of extreme and moderate ASEGs, functional division modes between embryo and extraembryonic tissues, and between paternal and maternal alleles. This study clarifies tissue-specific ASE patterns and mechanisms, providing a framework for future ASE research.
Blockade of FGFR1 Trafficking to the Cell Surface Results in the Partial Mistargeting of the Receptor to Peroxisomes.
Działek P, Chorążewska A, Biaduń M … +3 more , Qiu J, Porębska N, Opaliński Ł
FASEB J · 2026 Jul · PMID 42383990 · Full text
Fibroblast growth factor receptor 1 (FGFR1) is a cell surface receptor tyrosine kinase implicated in cellular signaling and homeostasis. Several reports indicate that N-glycosylation of FGFR1 is critical for the FGFR1 tr...
Fibroblast growth factor receptor 1 (FGFR1) is a cell surface receptor tyrosine kinase implicated in cellular signaling and homeostasis. Several reports indicate that N-glycosylation of FGFR1 is critical for the FGFR1 trafficking to the cell surface, as glycosylation-deficient mutant of FGFR1 (FGFR1.GF) is trapped inside the cell, in the endoplasmic reticulum (ER), and in the nuclear envelope. Our recent mass spectrometry analyses revealed dehydrogenase/reductase 2 (DHRS2) as a putative binding partner of the intracellular FGFR1.GF. Here, we identified a peroxisomal targeting signal 1 (PTS1) at the C-terminus of DHRS2 and demonstrated that DHRS2 is dually targeted to peroxisomes and mitochondria. Furthermore, we determined that knockdown of DHRS2 results in increased number of peroxisomes, implicating the role of DHRS2 in peroxisome biogenesis. Using proximity ligation assay (PLA), we confirmed the interaction between FGFR1.GF and DHRS2 and demonstrated that FGFR1.GF/DHRS2 complexes are predominantly detected in peroxisomes. In agreement, we detected a small fraction of FGFR1.GF in peroxisomes. Taken together our data indicate that accumulation of FGFR1.GF in the ER may result in FGFR1.GF targeting to peroxisomes. Furthermore, we reveal interconnection between FGFR1 and DHRS2 and their role in peroxisome biogenesis.
A Myocyte-Enriched Long Non-Coding RNA NRMLncR Enhances Myogenesis in Mouse.
Li Y, Zhou Y, Li QY … +10 more , Arrington J, Hu Z, Abdelhai MF, Wang Y, Ren J, Cheng YY, Xie M, Tao WA, Kuang S, Yue F
FASEB J · 2026 Jul · PMID 42383557 · Full text
Myogenesis is a stepwise process encompassing myogenic progenitor proliferation, lineage commitment, differentiation, myocyte fusion, and myotube maturation, and it is orchestrated by myogenic regulatory factors (MRFs) t...
Myogenesis is a stepwise process encompassing myogenic progenitor proliferation, lineage commitment, differentiation, myocyte fusion, and myotube maturation, and it is orchestrated by myogenic regulatory factors (MRFs) together with signaling pathways that coordinate these transitions. Long noncoding RNAs (lncRNAs) have emerged as important regulators of muscle development and regeneration, yet how lncRNAs integrate with canonical signaling networks to shape myogenic progression remains incompletely defined. Here, we identify a novel myocyte-enriched, Notch-repressed myogenic lncRNA (NRMLncR, known as A930003A15Rik), as a previously uncharacterized regulator of mouse myogenesis. The expression of NRMLncR is robustly induced during primary myoblast activation and differentiation. Loss-of-function analyses show that knockdown of NRMLncR impairs myogenic differentiation, accompanied by reduced expression of key myogenic genes. In contrast, adenovirus-mediated overexpression of NRMLncR enhances myogenic differentiation in vitro and is associated with increased muscle fiber size in vivo. Mechanistically, MyoD and MyoG occupy the NRMLncR promoter and promote its transcription during myogenic differentiation. NRMLncR knockdown alerts the transcription of nearby genes, suggesting its function through a cis-regulatory mechanism. RNA pull-down and functional assays further identify an interaction between NRMLncR and the RNA-binding protein CELF1. Together, these findings establish NRMLncR as a novel Notch-associated lncRNA that promotes myogenic differentiation and provide insight into lncRNA-dependent regulation of the myogenic program.
Domain-Specific Genotype-Phenotype Correlations in DNM1L Disorders: Insights Into Mutation Hotspots and Clinical Severity.
Liang H, Chen Z, Huang S … +3 more , Wei H, Xu J, Hu S
FASEB J · 2026 Jul · PMID 42381493 · Publisher ↗
DNM1L-related disorders are rare mitochondrial diseases characterized by defective fission dynamics, often presenting with severe neurological manifestations. Current diagnostic and prognostic challenges stem from incomp...
DNM1L-related disorders are rare mitochondrial diseases characterized by defective fission dynamics, often presenting with severe neurological manifestations. Current diagnostic and prognostic challenges stem from incomplete knowledge of domain-specific genotype-phenotype correlations and limited clinical data. We report a novel GTPase effector domain (GED) variant (p.Val687del) and conduct a systematic analysis of 80 reported DNM1L cases with variants in the GTPase, Middle, or GED domains. Clinical, genetic, and survival data were extracted and analyzed to evaluate associations between mutation localization and clinical outcomes. Statistical comparisons of phenotypic severity, survival, and hotspot prevalence were performed. Functional validation of the novel variant was performed through in vitro overexpression, Western blot, immunofluorescence, and transmission electron microscopy. A novel GED deletion (p.Val687del) associated with peripheral neuropathy was identified, expanding the mutational spectrum. In vitro functional studies confirmed that this variant impairs DRP1 mitochondrial localization and induces severe ultrastructural damage, including fragmentation, swelling, and vacuolation. The preserved protein expression level excludes haploinsufficiency, consistent with a dominant-negative mechanism. Within the total cohort of 81 patients (including our case), de novo variants were predominant (74.1%), with R403C representing a major mutational hotspot (28.4%). Middle domain mutations conferred the most severe prognosis, manifesting high frequencies of developmental delay (90.7%), epilepsy (83.7%), abnormal muscle tone (67.4%), abnormal EEG findings (74.4%), and cerebral atrophy (73.2%). In contrast, GTPase domain mutations primarily affected sensory pathways, with optic atrophy (57.6%) and peripheral neuropathy (27.3%) as hallmark features. Carriers of the R403C variant exhibited a 3.9-year delay in disease onset compared to non-carriers. This study establishes that mutation location in DNM1L dictates clinical severity, with Middle domain variants defining a severe encephalopathic subtype, while GTPase domain mutations predominantly target sensory pathways, leading to optic atrophy and peripheral neuropathy. These findings provide a framework for precision prognostication and targeted therapeutic strategies in DNM1L-related disorders.
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