FASEB Journal[JOURNAL]
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200 papers
Impaired NF-κB/Nrf2 Crosstalk in Rett Syndrome.
Cordone V, Vallese A, Bianchi A … +3 more , Guiotto A, Pecorelli A, Valacchi G
FASEB J · 2026 May · PMID 42159339 · Publisher ↗
Rett syndrome (RTT), caused primarily by mutations in the X-linked MECP2 gene, is a neurodevelopmental disorder marked by systemic alterations, including mitochondrial dysfunction, chronic oxidative stress, and persisten...
Rett syndrome (RTT), caused primarily by mutations in the X-linked MECP2 gene, is a neurodevelopmental disorder marked by systemic alterations, including mitochondrial dysfunction, chronic oxidative stress, and persistent subclinical inflammation. This OxInflammatory state suggests that disruption of redox-inflammatory regulatory pathways may contribute to disease pathophysiology. In this context, NF-κB and Nrf2 represent two important signaling regulators that operate in a coordinated crosstalk to balance inflammatory activation and antioxidant defense. In this study, we explored the functional status of NF-κB/Nrf2 crosstalk in primary dermal fibroblasts derived from RTT patients and healthy controls (CTR). Under basal conditions, RTT fibroblasts exhibited increased nuclear localization of NF-κB p65 and higher levels of acetylated NF-κB, indicating a constitutive inflammatory condition. In contrast, Nrf2 activation was not proportionally enhanced, suggesting an imbalance between inflammatory and antioxidant signaling. Following LPS stimulation, CTR fibroblasts displayed the expected coordinated activation of NF-κB and Nrf2 pathways, along with induction of downstream target genes. RTT fibroblasts, however, failed to activate either pathway and showed blunted transcriptional responses. These findings support the presence of a dysregulated signaling axis consistent with a chronic OxInflammatory state. Analysis of regulatory mechanisms revealed increased basal CBP/p300 levels in RTT cells without a compensatory increase in SIRT1, pointing toward altered acetylation dynamics that may favor persistent NF-κB activity. To mechanistically study the NF-κB/Nrf2 crosstalk, LPS-stimulated cells were treated with the Nrf2 activator sulforaphane (SFN), alone or combined with the NF-κB inhibitor BAY-117082. In RTT fibroblasts, these combined interventions significantly reduced pro-inflammatory cytokine expression and consistently enhanced HMOX1 transcription and HO-1 protein levels. Although nuclear localization changes were modest at the selected time point, downstream gene expression patterns indicated that coordinated modulation of inflammatory and antioxidant pathways can partially rebalance cellular responses. Taken together, our findings provide preliminary evidence that RTT exhibits a dysfunctional NF-κB/Nrf2 regulatory axis characterized by basal inflammatory activation and impaired antioxidant compensation. Modulation of NF-κB signaling, in combination with Nrf2 activation, may represent a promising strategy to counteract the persistent OxInflammatory milieu associated with RTT and warrants further investigation.
MMP14 Silencing Alleviates Inflammation-Associated Bone Loss in Chronic Periodontitis and Postmenopausal Osteoporosis in Association With Reduced JAK2/STAT3 Signaling.
Jiang X, Jia W, Ma Q … +2 more , Fan W, Luo S
FASEB J · 2026 May · PMID 42159331 · Publisher ↗
Chronic periodontitis (CP) and postmenopausal osteoporosis (PMOP) are prevalent chronic inflammatory diseases characterized by bone resorption; however, the shared molecular mechanisms between them remain unclear. Hub ge...
Chronic periodontitis (CP) and postmenopausal osteoporosis (PMOP) are prevalent chronic inflammatory diseases characterized by bone resorption; however, the shared molecular mechanisms between them remain unclear. Hub genes associated with CP and PMOP were identified through bioinformatics analysis. Lipopolysaccharide (LPS)-stimulated MC3T3-E1 osteoblasts were used to establish an in vitro model, followed by lentiviral-mediated matrix metalloproteinase 14 (MMP14) knockdown. Cell viability and apoptosis were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. Levels of inflammatory cytokines and oxidative stress markers were measured by enzyme-linked immunosorbent assay. Intracellular ROS were detected using 2',7'-dichlorodihydrofluorescein diacetate fluorescence staining. Western blot analysis was performed to assess the expression of osteoclast-related markers. The involvement of the JAK2/STAT3 pathway was assessed using the JAK2 agonist RO8191 and inhibitor AG490. PDGFRB, MMP14, VWF, PECAM1, FLT1, and CXCR4 were identified as hub genes and were all upregulated in LPS-stimulated MC3T3-E1 osteoblasts. Silencing MMP14 improved cell viability and reduced apoptosis, inflammatory cytokine release (TNF-α, IL-1β, and IL-6), oxidative stress markers (MDA and ROS), and osteoclast-associated markers (CTX-I, TRAP, and Cathepsin K), while restoring SOD activity. Mechanistically, MMP14 silencing decreased the phosphorylation levels of JAK2 and STAT3. The protective phenotype caused by MMP14 silencing was significantly abolished by RO8191 but mimicked by treatment with AG490. MMP14 may represent a potential molecular link between CP-associated bone loss and PMOP. Modulation of the MMP14-JAK2/STAT3 signaling axis may represent a promising research direction for inflammation-related bone loss.
Pirfenidone Elevates GLIS1 by Disrupting the USP7/DNMT1 Complex and Alleviates Renal Fibrosis in Diabetic Kidney Disease Through ROS Reduction and TGF-β1/Smad Signaling Inhibition.
Tu W, Hu L, Wu L … +3 more , Zhou H, Yang R, Chen Y
FASEB J · 2026 May · PMID 42159303 · Publisher ↗
Renal fibrosis is a pathological feature of advanced-stage diabetic kidney disease (DKD). Here, we investigated the effect of Pirfenidone (PFD) on renal fibrosis under diabetic conditions and its molecular mechanism. Sir...
Renal fibrosis is a pathological feature of advanced-stage diabetic kidney disease (DKD). Here, we investigated the effect of Pirfenidone (PFD) on renal fibrosis under diabetic conditions and its molecular mechanism. Sirius red staining and immunohistochemistry were used for histological analysis in rat kidney. Levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected by kits. Lipid hydroperoxide, malondialdehyde (MDA), glutathione peroxidase (GPX), and superoxide dismutase (SOD) were measured by commercial kits. Immunofluorescence staining was used to evaluate the expression and colocalization of USP7 and DNMT1. Mitochondrial and cytoplasmic reactive oxygen species (ROS) levels were detected. GLIS1, DNMT1, and USP7 mRNA were measured by RT-qPCR. Protein levels of DNMT1, USP7, fibronectin, p-Smad2, Smad2, p-Smad3, and Smad3 were detected by Western blot. Methylation of the GLIS1 promoter was assessed utilizing methylation-specific polymerase chain reaction (MSP). Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) verified molecular interactions. PFD alleviated renal injury and fibrosis in DKD rats by suppressing TGF-β1/Smad signaling. PFD attenuated renal oxidative stress and mitochondrial dysfunction in DKD rats. GLIS1 knockdown reversed PFD's protective effects in high glucose (HG)-exposed HK-2 cells, abolishing its improvements in oxidative stress, mitochondrial function, and fibrosis. PFD attenuated HG-induced GLIS1 promoter hypermethylation by suppressing DNMT1 binding and activity, thereby restoring GLIS1 expression. PFD suppressed DNMT1 activity by disrupting USP7/DNMT1 complex. Importantly, the USP7/DNMT1 axis mediated the regulatory effect on GLIS1, which subsequently counteracted PFD's protective effects on HG-stimulated HK-2 cells. PFD upregulates GLIS1 by disrupting the USP7/DNMT1 complex, which subsequently suppresses the ROS/TGF-β1/Smad pathway to alleviate renal fibrosis in DKD. This study identifies the USP7/DNMT1/GLIS1 epigenetic axis as a critical upstream mechanism driving the protective effects of PFD, providing new therapeutic targets for DKD treatment.
Mechanistic Study on MSC-EXO Loaded with Salubrinal for the Treatment of Osteomyelitis-Induced Bone Defects.
Yue X, Song X, Wu J … +6 more , Liu Z, Wang Y, Chen G, Li W, Tan H, Yang K
FASEB J · 2026 May · PMID 42159260 · Publisher ↗
Osteomyelitis-related bone defects arise from bacterial infection-induced tissue damage and inadequate repair, resulting in pain, swelling, and functional loss. Here, we evaluated locally delivered salubrinal-loaded mese...
Osteomyelitis-related bone defects arise from bacterial infection-induced tissue damage and inadequate repair, resulting in pain, swelling, and functional loss. Here, we evaluated locally delivered salubrinal-loaded mesenchymal stem cell-derived exosomes (Sal-MSC-exo) in a rat model of infectious osteomyelitis. After characterizing MSCs, their exosomes, and drug-loading efficiency, we established a Staphylococcus aureus-induced osteomyelitis model and assigned rats to five groups: control, infected, salubrinal (Sal), exosome (Exo), and Sal-MSC-exo. Outcomes included histology and micro-CT, osteoblast proliferation (EdU), ER ultrastructure (electron microscopy), immunohistochemistry, Western blotting, and cell migration assays (transwell and scratch). These analyses assessed osteoblast proliferation and apoptosis, ER-stress signaling, extracellular matrix proteins, autophagy-related markers, and inflammatory activation. Sal-MSC-exo partially restored trabecular architecture, suppressed osteoblast apoptosis, and enhanced osteoblast migration compared with infected controls and single-agent groups. Mechanistically, Sal-MSC-exo attenuated ER stress, evidenced by upregulation of p-eIF2α and ATF4 with concomitant reduction of CHOP. In parallel, Sal-MSC-exo modulated autophagy-associated with increased p-eIF2α, eIF2α, LC3-I/II, and ALP and reduced p62-consistent with relief of maladaptive ER-stress-autophagy cross talk. Collectively, these findings indicate that Sal-MSC-exo mitigates osteomyelitis-associated bone loss and supports bone repair, highlighting its translational potential as a localized therapy for infection-induced bone defects.
Lifestyle Modulation of Xenobiotic Stress: Aerobic Exercise Attenuates Nanoplastic-Associated Neuroendocrine Dysfunction via a Gut-Ovary-Brain Continuum.
Xu H, Xu B, Wang H … +6 more , Tao R, Chen R, Cheng Y, Zheng Z, Sun D, Li X
FASEB J · 2026 May · PMID 42157753 · Publisher ↗
Xenobiotic stress can disrupt neuroendocrine function, yet whether a modifiable lifestyle factor can alter internal burden and downstream toxicity remains unclear. Here, adult female zebrafish were exposed to polystyrene...
Xenobiotic stress can disrupt neuroendocrine function, yet whether a modifiable lifestyle factor can alter internal burden and downstream toxicity remains unclear. Here, adult female zebrafish were exposed to polystyrene nanoplastics (NPs; 80 nm; 1.0 mg/L) for 21 days, with or without moderate aerobic exercise (AE; 12 cm/s, 20 min/day). NPs exposure alone caused significant ovarian accumulation of particle-like structures (TEM), elevated oxidative stress, increased follicular apoptosis (TUNEL), and disrupted reproductive hormones (E2, FSH, LH). It also induced anxiety- and depression-like behaviors in novel tank and shoaling tests, accompanied by elevated cortisol and altered monoamine (NE, 5-HIAA) levels. In contrast, concurrent AE markedly attenuated these effects: it reduced ovarian particle burden, improved antioxidant enzyme activities (SOD, POD), restored ovarian histoarchitecture, and normalized endocrine and neuroendocrine measures. These changes were supported by partial recovery of ovarian (ESR1, cyp19a1a, AMH) and brain (BDNF, TPH2) transcript levels. Gut microbiome profiling revealed that AE counteracted NPs-associated dysbiosis, enriching beneficial taxa, including Akkermansia and Lachnospiraceae_NK4A136_group. Predictive functional inference and correlation analyses linked these microbial shifts to enhanced fatty acid and tryptophan metabolic potential, which correlated with neuroendocrine recovery. Together, these data support a working model in which AE acts as an exposure modifier, coupling host physiology and microbiome-associated metabolic capacity to mitigate NPs-induced neuroendocrine dysfunction via a gut-ovary-brain continuum. Targeted metabolomics and causal microbiota perturbation will be needed to validate specific mediators.
RETRACTION: Physiological Levels of Amyloid Peptides Stimulate the Angiogenic Response Through FGF-2.
FASEB J · 2026 May · PMID 42157638 · Publisher ↗
S. Cantara, S. Donnini, L. Morbidelli, A. Giachetti, R. Schulz, M. Memo and M. Ziche, "Physiological Levels of Amyloid Peptides Stimulate the Angiogenic Response Through FGF-2," The FASEB Journal 18, no. 15 (2004): 1943-...
S. Cantara, S. Donnini, L. Morbidelli, A. Giachetti, R. Schulz, M. Memo and M. Ziche, "Physiological Levels of Amyloid Peptides Stimulate the Angiogenic Response Through FGF-2," The FASEB Journal 18, no. 15 (2004): 1943-1945, https://doi.org/10.1096/fj.04-2114fje. The above article, published online on 24 September 2004 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Dr. Loren E. Wold; the Federation of American Societies for Experimental Biology; and Wiley Periodicals, LLC. The journal received allegations by a third party of image manipulation present in Figure 4E. Further investigation of the article confirmed the third-party concerns and also detected evidence of additional reuse and relabeling in Figures 2A, 3C, and 4D and undisclosed splicing in Figure 4D. The retraction has been agreed to because of the evidence of image manipulation and duplication in multiple figures, which fundamentally compromises the editors' confidence in the conclusions presented. The authors disagree with the retraction.
LAPTM5 Promotes Age-Related Renal Fibrosis via USP10/PTEN-Mediated Autophagy Inhibition.
Wang Y, Gu Q, Chen X … +5 more , Yang X, Zhai J, Kang M, Wu J, Zhao W
FASEB J · 2026 May · PMID 42149696 · Publisher ↗
Aging accelerates renal fibrosis driven by renal tubular epithelial cells (RTECs) senescence. However, the underlying molecular mechanisms remain elusive. We demonstrate that lysosomal transmembrane protein 5 (LAPTM5) is...
Aging accelerates renal fibrosis driven by renal tubular epithelial cells (RTECs) senescence. However, the underlying molecular mechanisms remain elusive. We demonstrate that lysosomal transmembrane protein 5 (LAPTM5) is markedly upregulated in aged kidney models and correlates with renal senescence and fibrosis severity. Mechanistically, LAPTM5 drives RTECs epithelial-mesenchymal transition (EMT) by interacting with USP10 and facilitating its lysosomal degradation, thereby relieving PTEN-mediated inhibition of the PI3K/AKT/mTOR-mediated autophagy pathway. This accelerates kidney fibrosis. Functionally, PTEN overexpression rescues LAPTM5-induced EMT in RTECs, while the PTEN agonist sophocarpine ameliorates renal fibrosis and preserves function in D-galactose-induced progeroid mice by restoring autophagy. Our findings identify the LAPTM5-USP10-PTEN axis as a critical regulator of autophagy-mediated renal fibrosis in aging kidney.
Macrophage-Fibroblast Crosstalk Shapes Wound Repair Signaling In Vitro.
Enriquez-Ochoa D, Nagalla RR, Liu Y … +10 more , Guerrero-Juarez CF, Atcha H, Chang G, Morales NA, Hooper HJ, Cano AD, Lim HE, Cahalan MD, Plikus MV, Liu WF
FASEB J · 2026 May · PMID 42149092 · Full text
Wound healing requires coordinated interactions between macrophages and fibroblasts, yet how contact-dependent signaling integrates with paracrine pathways to regulate their reciprocal behavior is not well defined. Here,...
Wound healing requires coordinated interactions between macrophages and fibroblasts, yet how contact-dependent signaling integrates with paracrine pathways to regulate their reciprocal behavior is not well defined. Here, we investigated macrophage-fibroblast communication using complementary 2D and 3D in vitro wound healing models combined with live-cell calcium imaging and single-cell RNA sequencing (scRNA-seq). We show that bone marrow-derived macrophages (BMDMs) promote fibroblast scratch closure in a contact-dependent manner independent of connexins, whereas fibroblasts reciprocally regulate macrophage cytokine secretion through distinct mechanisms. Direct cell-cell contact with fibroblasts enhanced macrophage IL10 production via connexin 43 (Cx43)-dependent signaling, whereas TNFα secretion was suppressed through paracrine interactions. We further demonstrate that fibroblast-macrophage contact induces connexin-dependent intermittent calcium signals selectively in macrophages. ScRNA-seq revealed that wounding reshapes macrophage and fibroblast populations, uncovering dynamic regulation of cell adhesion molecules (CAMs) and intercellular signaling pathways. Together, these findings reveal the integration of contact-dependent calcium and connexin signaling with transcriptional remodeling to coordinate macrophage-fibroblast behavior during healing.
NINJ1-Mediated Plasma Membrane Rupture in Lytic Cell Death: Mechanisms, Consequences, and Context.
El-Moaty ZA, Hamad RS, Ali MAM … +9 more , Elmorsy EA, Shata A, Nassar GM, Morsy NE, Ibrahim S, Hamouda MA, El Sabaa RM, Chaudhary AA, Saber S
FASEB J · 2026 May · PMID 42149040 · Publisher ↗
Lytic cell death has long been interpreted as a terminal consequence of inflammasome activation, gasdermin cleavage, and osmotic membrane failure. Recent evidence supports a more differentiated cellular model in which ea...
Lytic cell death has long been interpreted as a terminal consequence of inflammasome activation, gasdermin cleavage, and osmotic membrane failure. Recent evidence supports a more differentiated cellular model in which early membrane permeabilization and terminal plasma membrane rupture are distinct events. However, these processes are still frequently treated as a single continuum, and a unifying framework that separates and integrates them across lytic death pathways is lacking. Within this revised framework, ninjurin 1 (NINJ1) has emerged as the best-supported mediator of plasma membrane rupture during terminal lytic cell death. Studies in pyroptosis, post-apoptotic lysis, ferroptosis, and related necrotic settings indicate that NINJ1 is not required for inflammasome assembly, gasdermin processing, or early cytokine release, but is crucial for terminal membrane disruption and release of large intracellular contents. Structural, biochemical, and imaging data further show that NINJ1 transitions from an autoinhibited membrane-associated state to higher order assemblies that destabilize or excise plasma membrane regions. These findings support a staged model of lytic death in which gasdermin pores establish a permeabilized state, whereas NINJ1 drives the final disintegration of the cell surface. Across these contexts, NINJ1 is best viewed as a convergent membrane-rupture effector that defines a distinct downstream layer of lytic cell death rather than a pathway-restricted component. This distinction has important implications for understanding how membrane rupture shapes cell morphology, extracellular release patterns, and tissue injury. By integrating evidence across lytic death programs, this review advances a unified framework in which permeabilization and terminal rupture are mechanistically separable, differentially regulated processes.
An Evolutionarily Conserved Function of Grainyhead in Orchestrating Insect Wing Development.
Du T, He J, Wang Y … +5 more , Xie X, Chen J, Xu Z, Zhou C, Sun W
FASEB J · 2026 May · PMID 42148710 · Publisher ↗
The development of insect appendages is governed by deeply conserved genetic programs, even as developmental strategies diverge widely across taxa. In this study, we identify the conserved transcription factor Grainyhead...
The development of insect appendages is governed by deeply conserved genetic programs, even as developmental strategies diverge widely across taxa. In this study, we identify the conserved transcription factor Grainyhead (Grh) as a crucial regulator of insect wing development. In the silkworm Bombyx mori, CRISPR/Cas9-mediated knockout of BmGrh did not compromise larval viability but resulted in severe wing defects in adults, including crumpled and non-expandable wings. Similarly, tissue-specific knockdown of DmGrh in Drosophila melanogaster wing imaginal discs led to pupal lethality, a sex-biased eclosion rate, and adults exhibiting crumpled wings with disrupted wing hair polarity. Comparative transcriptomics revealed that loss of DmGrh function predominantly downregulates genes associated with cuticle structure and extracellular matrix organization in both species. In Drosophila, chromatin immunoprecipitation further confirmed that DmGrh directly binds to regulatory regions of these downregulated cuticle-related genes. Through functional screening, we identified the cuticle protein gene cpr65Ea as a key downstream effector, whose knockdown recapitulated the wing morphogenesis and eclosion defects observed in DmGrh RNA interference individuals. Moreover, extending our investigation to an agricultural pest, RNAi-mediated silencing of SfGrh in the white-backed planthopper (Sogatella furcifera) impaired wing expansion and completely abolished flight ability. Our findings establish Grh as an evolutionarily conserved regulator of insect wing development and highlight its potential as a novel genetic target for pest management by disrupting flight capacity and dispersal.
Mts/PP2AC Induces Cell Migration via Rho1-Slpr-Mediated JNK Pathway.
Zhang W, Zhu J, Ouyang X … +1 more , Dong B
FASEB J · 2026 May · PMID 42144974 · Publisher ↗
Cell migration plays crucial roles in cancer generation and metastasis. A deeper understanding of the mechanisms that govern this migratory behavior may uncover novel drug targets that could be utilized in cancer treatme...
Cell migration plays crucial roles in cancer generation and metastasis. A deeper understanding of the mechanisms that govern this migratory behavior may uncover novel drug targets that could be utilized in cancer treatments. PP2AC, the catalytic subunit of protein phosphatase 2A, has been found to be expressed in various human cancers. However, the specific role of PP2AC in the context of cancer cell migration has remained elusive. In this study, we demonstrated that Mts (the ortholog of PP2AC in Drosophila) is sufficient to trigger cell migration through activating the JNK pathway. Genetic epistasis analyses data revealed that Mts acts upstream of Slpr in the JNK signaling cascade. Furthermore, we identified Rho1 as a candidate mediator through affinity purification-mass spectrometry (AP-MS), which functions downstream of Mts in the Slpr-JNK signaling cascade supported by genetic evidence. Consistently, our results revealed that Mts activates the JNK signaling pathway by increasing the protein level of Rho1. Finally, we showed that PP2AC promotes cell migration in human pancreatic adenocarcinoma (PAAD) cells and is associated with RhoA levels and JNK activation. Taken together, our research supports a model in which Mts/PP2AC functions as an upstream regulator of the Rho1-JNK signaling axis in cell migration and offers promising therapeutic strategies to combat cancer metastasis.
Yap/Taz Orchestrates Chondrocyte Differentiation Fate in Fibrocartilage Development.
Liu Y, Wang X, Wang J … +3 more , Tang H, He Y, Chen S
FASEB J · 2026 May · PMID 42144968 · Publisher ↗
The condyle is a key growth center of the mandible, covered by a layer of fibrocartilage. Through endochondral ossification, condylar cartilage drives mandibular elongation and height increase. However, the precise regul...
The condyle is a key growth center of the mandible, covered by a layer of fibrocartilage. Through endochondral ossification, condylar cartilage drives mandibular elongation and height increase. However, the precise regulatory mechanism underlying this process remains unclear. In this study, we employed Aggrecan(Acan)-Cre;Yap;Taz mice to investigate the consequences of Yap/Taz deletion on chondrocyte differentiation and endochondral ossification during postnatal fibrocartilage development. Histological analysis revealed that the loss of Yap/Taz reduced the proportions of the superficial and proliferative zones but increased that of the hypertrophic layer. Micro-CT analysis further showed that condylar height and subchondral bone formation were significantly decreased. Col X+ hypertrophic chondrocytes exhibited a stacked arrangement, yet failed to support endochondral ossification. Mechanistically, deletion of Yap/Taz likely suppresses Runx2 expression, thereby impairing the transdifferentiation potential of hypertrophic chondrocytes into osteoblasts. Collectively, these findings demonstrate that Yap/Taz inhibits chondrocyte maturation during chondrocyte differentiation while promoting chondrocyte transdifferentiation into osteoblasts at the subsequent endochondral ossification stage.
Chronic Cholestatic Liver Disease Induced by Larval Ascariasis: Novel Insights Into Immune-Mediated Pathogenesis and Hepatic Fibrosis in Mice.
Souza JLN, Amorim CCO, Antunes-Porto AR … +14 more , Souza FR, Oliveira EA, da Silva Oliveira I, de Brito Duval I, Saldanha-Elias AM, Cardozo ME, de Medeiros Brito RM, Magalhães LMD, Cassali GD, Briggs N, Fujiwara RT, Russo RC, Cançado GGL, Bueno LL
FASEB J · 2026 May · PMID 42144944 · Full text
Ascariasis is a widespread helminthic infection, yet the long-term hepatic consequences of larval migration remain poorly understood. Evidence indicates that tissue damage may persist beyond parasite clearance. While chr...
Ascariasis is a widespread helminthic infection, yet the long-term hepatic consequences of larval migration remain poorly understood. Evidence indicates that tissue damage may persist beyond parasite clearance. While chronic cholestatic liver disease is classically associated with obstructive, autoimmune, or genetic disorders, parasitic infections such as ascariasis may represent an overlooked etiology. This study investigated post-migratory hepatic effects of Ascaris suum larvae in a mouse model, evaluating dose-dependent and exposure-frequency paradigms. Female BALB/c mice were infected with A. suum eggs using low-dose (250 eggs) or high-dose (2500 eggs), administered as single or reinfection (14 days apart). Mice were euthanized at three time points, day 4 post-infection (dpi) (peak hepatic migration phase), or 35 and 100 dpi (post-hepatic clearance). Livers were analyzed for parasite burden (4 dpi), cytokine gene expression, and comprehensive histopathological analysis (35/100 dpi). Plasma was assessed for biochemical markers (AST, ALT, GGT, ALP, total bilirubin and fractions, and albumin) and cytokine quantification. Histological analysis revealed persistent hepatic inflammation and fibrotic remodeling up to 100 dpi. Biochemical assays confirmed cholestatic dysfunction with elevated ALP, GGT, and bilirubin. Gene expression analysis showed sustained inflammatory signaling. These findings establish that larval migration induces chronic hepatobiliary injury and cholestasis, independent of peak burden. Importantly, pathology occurred without adult worm-mediated biliary obstruction, identifying a novel helminth-driven hepatic disease mechanism. Our findings demonstrated that ascariasis, even at low infection intensities and in the absence of adult worm establishment, can induce persistent hepatic inflammation, fibrotic progression, and cholestatic dysfunction. This evidence challenges the prevailing paradigm that biliary obstruction by adult worms is the exclusive mechanism of hepatobiliary injury in ascariasis. Our results underscore the significant pathogenic potential of larval stages and their ability to provoke chronic liver pathology that persists well beyond parasite clearance. These observations are clinically relevant for endemic regions, where recurrent low-level exposure may lead to cumulative liver damage despite the absence of overt adult worm infection.
Intravesical Delivery of P21 mRNA-Loaded Lipid Nanoparticles as a Tumor Suppressor Replacement Therapy for Bladder Cancer.
Zeng J, Cao Z, Wang C … +1 more , Xu Y
FASEB J · 2026 May · PMID 42144924 · Full text
Bladder cancer is characterized by high recurrence rates and limited long-term benefit from current intravesical therapies, highlighting the need for alternative localized treatment strategies. Among tumor suppressors al...
Bladder cancer is characterized by high recurrence rates and limited long-term benefit from current intravesical therapies, highlighting the need for alternative localized treatment strategies. Among tumor suppressors altered in bladder cancer, CDKN1A, which encodes the cyclin-dependent kinase inhibitor p21, is recurrently inactivated and downregulated, supporting its potential as a target for tumor suppressor replacement. Here, we developed a non-viral therapeutic strategy based on chemically modified p21 mRNA encapsulated in lipid nanoparticles (p21-LNP) for intravesical delivery. Public dataset analysis, tissue microarray staining, and cell line validation showed that p21 expression decreases during bladder cancer progression and that endogenous p21 protein levels are very low in bladder cancer cells. In vitro, synthetic p21 mRNA achieved robust nuclear p21 expression and markedly suppressed bladder cancer cell proliferation, viability, and clonogenicity. Mechanistically, p21 restoration reduced retinoblastoma protein (Rb) phosphorylation, decreased Cyclin E, Cyclin B, and proliferating cell nuclear antigen (PCNA) expression, increased γ-H2A.X accumulation, and promoted apoptosis. The resulting p21-LNP showed favorable physicochemical properties for intravesical administration. In vivo, reporter mRNA-LNP mediated strong bladder-localized protein expression with limited and transient systemic distribution. In an orthotopic bladder cancer mouse model, repeated intravesical administration of p21-LNP significantly suppressed tumor growth, restored p21 expression in bladder tissues, and preserved urothelial architecture without obvious adverse effects. Together, these findings establish intravesical delivery of p21 mRNA-LNP as a clinically compatible strategy for localized tumor suppressor replacement therapy in bladder cancer.
Structural and Functional Basis of SSTR5 Homodimerization in Controlling Receptor Signaling and Pasireotide Response in Corticotroph Adenomas.
Zhou H, Li C, Gu W … +10 more , Feng Y, Li X, Chen D, Liu Y, Liu F, Cheng Y, Xu C, Tang H, Wu ZB, Xue L
FASEB J · 2026 May · PMID 42141916 · Publisher ↗
Somatostatin receptor subtype 5 (SSTR5), a G protein-coupled receptor (GPCR) highly expressed in the pituitary gland, plays a pivotal role in regulating adrenocorticotropic hormone (ACTH) secretion. While SSTR5 homodimer...
Somatostatin receptor subtype 5 (SSTR5), a G protein-coupled receptor (GPCR) highly expressed in the pituitary gland, plays a pivotal role in regulating adrenocorticotropic hormone (ACTH) secretion. While SSTR5 homodimerization has been observed in heterologous expression systems, its in situ existence, structural dynamics, and functional relevance in clinical pathology remain elusive. In this study, we provide the first evidence of endogenous SSTR5 homodimers in human corticotroph adenomas. Further analysis reveals that SSTR5 dimerization is mediated by multiple transmembrane (TM) interfaces and, uniquely among GPCRs, lacks ligand-induced conformational rearrangement. Functionally, we demonstrate that a stabilized dimeric conformation induces signaling bias by impairing both constitutive Gi protein activation and agonist-induced beta-arrestin2 recruitment. In cellular models of corticotroph adenomas, SSTR5 dimerization significantly attenuates the receptor's capacity to suppress hormone secretion and diminishes responsiveness to the clinical agonist pasireotide. Furthermore, we identified a natural genetic variant (V270I) that modulates dimerization efficiency, potentially serving as a biomarker for therapeutic sensitivity. Collectively, these findings establish SSTR5 homodimerization as a critical determinant of receptor signaling and a key modulator of pharmacological efficacy in the treatment of corticotroph adenomas.
The m6A Reader IGF2BP2 Regulates Schwann Cell Autophagy and Neurotrophin Expression via EGR1 in Diabetic Peripheral Neuropathy.
Wei W, Li F, Jin T … +7 more , Li Q, Gao Y, Yuwen C, Sun Y, Li W, Zhu L, Hao J
FASEB J · 2026 May · PMID 42141912 · Publisher ↗
Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus, and Schwann cell dysfunction contributes to its pathogenesis and progression. IGF2BP2 is a single-stranded RNA-binding protein t...
Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus, and Schwann cell dysfunction contributes to its pathogenesis and progression. IGF2BP2 is a single-stranded RNA-binding protein that has recently been identified as an m6A reader; however, its role and regulatory effects in Schwann cells during DPN remain largely unknown. In this study, we demonstrated that high-glucose exposure significantly increased IGF2BP2 levels in RSC96 cells and in the sciatic nerves of both type 1 and type 2 diabetic mice, accompanied by reduced autophagy and neurotrophin expression. Consistently, IGF2BP2 expression was associated with metabolic and immune-related parameters in patients with type 2 diabetes. Functionally, IGF2BP2 overexpression inhibited, whereas its downregulation partially rescued, high glucose-induced suppression of autophagy and neurotrophin expression in vitro (RSC96 cells) and in vivo (IGF2BP2 knockout mice). Mechanistically, IGF2BP2 bound to EGR1 mRNA in an m6A modification-dependent manner, primarily recognizing an adenosine at position 1268, thereby enhancing EGR1 mRNA stability. Downregulation of EGR1 alleviated the inhibitory effects of IGF2BP2 overexpression on autophagy and neurotrophin expression in RSC96 cells. Conversely, EGR1 overexpression attenuated the protective effects of IGF2BP2 knockout on peripheral nerve function and neurotrophic signaling in diabetic mice. Overall, high-glucose stimulation upregulated IGF2BP2, which enhanced EGR1 mRNA stability in an m6A-dependent manner, thereby suppressing autophagy and neurotrophin expression in Schwann cells during DPN.
Differential Immune Cell Distribution Between Arterial and Venous Blood in Healthy Rats.
Lai S, Li L, Yang S … +2 more , Jia S, Cui Q
FASEB J · 2026 May · PMID 42141902 · Publisher ↗
We previously identified differentially expressed miRNAs between arterial and venous blood in rats; however, whether immune cell composition and transcriptional states differ along the arterial-venous axis remains unclea...
We previously identified differentially expressed miRNAs between arterial and venous blood in rats; however, whether immune cell composition and transcriptional states differ along the arterial-venous axis remains unclear. Here, single-cell RNA sequencing of 119 481 PBMCs, complemented by flow cytometry and protein-level validation, was performed to characterize immune heterogeneity between arterial and venous blood. Cell composition analysis showed enrichment of T cells in arterial blood, whereas B cells, NK cells, and monocytes were more abundant in venous blood. At the subset level, naïve T cells were enriched in arterial blood, while CD8 effector memory T cells were increased in venous blood. NK cell analysis demonstrated enrichment of cytotoxic NK subsets in venous blood and resting NK subsets in arterial blood, whereas monocyte subset proportions were comparable between compartments. Transcriptomic analysis revealed reduced JAK-STAT signaling in venous PBMCs, consistent with decreased STAT3 and NF-κB phosphorylation. Subset-specific analysis further showed reduced TNF/NF-κB signaling and enrichment of ribosome-associated pathways in venous T cells, enhanced cytotoxic, chemokine, and NF-κB-related programs in venous NK cells, and attenuated TNF/NF-κB signaling with increased ribosome-associated activity in monocytes, indicating functional reprogramming without compositional changes. Collectively, these findings demonstrate coordinated but cell type-specific immune adaptations along the arterial-venous axis, identifying blood sampling site as a critical determinant of immune readouts and a previously underappreciated source of variability in immunological studies.
Correction to "Belzutifan Attenuates Choroidal Neovascularization by Suppressing the HIF-2α/PAI-1 Axis".
FASEB J · 2026 May · PMID 42139052 · Publisher ↗
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Targeting DECR1 Mitigates Ferroptosis in Airway Epithelial Cells and Promotes Inflammation Resolution in Asthma.
Yuan X, Wang M, Li J … +4 more , Sun P, Fu H, Yao L, Yao X
FASEB J · 2026 May · PMID 42139047 · Publisher ↗
Asthma is characterized by persistent airway inflammation, and ferroptosis is closely related to this pathological manifestation. Although studies have explored the inducing factors of asthmatic inflammation, the regulat...
Asthma is characterized by persistent airway inflammation, and ferroptosis is closely related to this pathological manifestation. Although studies have explored the inducing factors of asthmatic inflammation, the regulatory mechanisms during the resolution phase and the role of ferroptosis in it remain unclear. In this study, proteomics was performed to characterize functional alterations in intrapulmonary airway epithelial cells during the resolution phase in an ovalbumin (OVA)-induced inflammation mouse model. The correlations among DECR1, ferroptosis, and airway inflammation were analyzed. The effects of DECR1 knockdown on ferroptosis and epithelial function, and the regulatory mechanism were examined in vitro. The impact of recombinant DECR1 administration and adeno-associated virus (AAV)-mediated DECR1 overexpression on inflammation resolution was evaluated in vivo. Finally, DECR1 levels in asthma patients were measured and correlated with clinical parameters. We demonstrated that the proteome underwent significant changes during the inflammation resolution phase in mice with OVA-induced airway inflammation, with DECR1 showing a marked decrease at the peak of inflammation and recovered during resolution. DECR1 levels were negatively correlated with airway inflammation and ferroptosis-associated markers. In vitro, our results confirmed that DECR1 deficiency induced ferroptosis and disrupted epithelial function by upregulating DUOXA1. In vivo, recombinant DECR1 administration or AAV-mediated DECR1 overexpression alleviated airway inflammation and accelerated resolution through mediating epithelial ferroptosis. Consistently, DECR1 levels were also reduced in asthma patients and positively correlated with lung function. Together, DECR1 regulates epithelial ferroptosis through DUOXA1-dependent mechanisms, thereby preserving epithelial integrity and promoting inflammation resolution. Targeting DECR1 may offer a novel therapeutic strategy for asthma.
Empagliflozin Restores the Colonic Mucous Barrier by an AMPK/SOX4-Dependent Pathway in Glycogen Storage Disease Type Ib.
Ma N, Zeng Y, Yang J … +8 more , Wang Y, Wu H, Li Z, Zhang X, Zeng H, Zhang Y, Yang M, Lan J
FASEB J · 2026 May · PMID 42133539 · Publisher ↗
Glycogen storage disease type Ib (GSD-Ib) is commonly associated with refractory inflammatory bowel disease (GSD-IBD). Although the SGLT2 inhibitor empagliflozin has demonstrated remarkable clinical efficacy, its direct...
Glycogen storage disease type Ib (GSD-Ib) is commonly associated with refractory inflammatory bowel disease (GSD-IBD). Although the SGLT2 inhibitor empagliflozin has demonstrated remarkable clinical efficacy, its direct effects on the intestinal epithelium remain poorly understood. This study aimed to determine whether empagliflozin directly restores the impaired colonic mucus barrier and to identify the underlying molecular pathway. In terms of efficacy, we integrated clinical evaluations of GSD-IBD patients with a novel murine model of epithelial injury induced by a defined bacterial consortium (EVS: Enterococcus, Veillonella, Streptococcus) and dextran sulfate sodium (DSS). In vitro, we employed Caco-2 cells and intestinal organoids, combined with pharmacological inhibition of AMPK and siRNA-mediated gene knockdown to elucidate the underlying molecular mechanisms. Clinical data indicated that empagliflozin promoted ulcer healing and enhanced mucin production in patients. In the EVS + DSS mouse model, empagliflozin treatment reduced disease severity and attenuated goblet cell depletion. We demonstrated that empagliflozin upregulates the transcription factor SOX4 in intestinal epithelial cells both in vivo and in vitro, an effect dependent on AMPK activation. Notably, siRNA knockdown of SOX4 abolished empagliflozin-induced MUC2 upregulation. Furthermore, pharmacological inhibition of AMPK suppressed the induction of MUC2, which could be rescued by SOX4 overexpression. Our findings uncover a novel, epithelium-intrinsic mechanism of action for empagliflozin: the activation of the AMPK/SOX4/MUC2 signaling axis to restore the colonic mucus barrier. These results provide a mechanistic foundation for the repurposing of SGLT2 inhibitors in conditions characterized by epithelial barrier dysfunction.
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