FASEB Journal[JOURNAL]
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200 papers
Novel Biomaterial-Based Synovial Fluid Analysis Reveals Protective microRNA Signatures in a Mouse Model of Acute Synovitis-Driven Osteoarthritis.
Takahata K, Arakawa K, Yasuda T … +4 more , Enomoto S, Katashima T, Sakai T, Kokubun T
FASEB J · 2026 Jun · PMID 42328732 · Full text
Acute synovitis and continuous mechanical stress are critical factors of Post-traumatic Osteoarthritis (PTOA); however, the effect on cartilage degeneration and its underlying mechanisms remains unclear. Here, we establi...
Acute synovitis and continuous mechanical stress are critical factors of Post-traumatic Osteoarthritis (PTOA); however, the effect on cartilage degeneration and its underlying mechanisms remains unclear. Here, we established a novel biomaterial-based method for synovial fluid analysis in mice to uncover the mechanisms underlying the onset of PTOA, focusing on synovitis and mechanical stress. Twelve-week-old C57BL/6J males were divided into the ACL-Transection (ACL-T), ACL-rupture (ACL-R), and Intact groups. We performed a joint instability test and histological analysis for cartilage degeneration and synovitis at 2, 6, and 10 weeks. Real-time PCR was performed on articular cartilage at 2 weeks and synovium at 2, 6, and 10 weeks. Tetra-slime was injected into the knee joint, and solidified slime containing synovial fluid molecules was analyzed in digital PCR at 2 weeks. Acute synovitis and cartilage degeneration were induced in the ACL-T group at 2 weeks, although no difference was observed in joint instability between the two ACL injury models. Real-time PCR showed a significant increase in Mmp-3, Tnf-α, Ifn-γ, and inos in the synovium of the ACL-T group. During this tissue interaction, although there were no significant differences, miR145-5p and miR149-5p in synovial fluid were also upregulated in the ACL-T group compared to the ACL-R group. Unlike the early stage, no histological or biological differences were observed between groups at 6 and 10 weeks. In conclusion, acute synovitis caused secondary cartilage degeneration via MMP-3 and TNF-α in the synovium during the early stage and may involve M1 macrophage activation. Whereas it was suggested that synovial fluid miRNA might be produced to suppress the secondary cartilage degeneration. Furthermore, mechanical stress was the dominant factor in the late stage of OA, regardless of the initial synovitis condition.
Beyond Hemostasis: Platelet Biomarkers and Vascular-Immune Crosstalk in Dengue.
da Silva-Alencar ABA, Matos AO, de Sousa DF … +4 more , Dietz JDC, Hottz ED, da Silva-Sales MFM, Sales-Campos H
FASEB J · 2026 Jun · PMID 42328715 · Full text
Dengue is an arboviral disease with major global public health impact. Its pathophysiology involves complex interactions between the virus and the host, including the immune response and the vascular endothelium. In this...
Dengue is an arboviral disease with major global public health impact. Its pathophysiology involves complex interactions between the virus and the host, including the immune response and the vascular endothelium. In this context, platelets play roles beyond hemostasis, acting as key immunomodulatory cells involved in inflammation and the regulation of vascular permeability. Therefore, this review summarizes and discusses the so called classic and non-classic platelet-related and endothelial biomarkers described in dengue virus infection. Classical biomarkers include P-selectin (CD62P), PF4/CXCL4, RANTES/CCL5, CD40L, IL-1β, VEGF, integrin αIIbβ3, CD63, and platelet extracellular vesicles, all supported by broad experimental and clinical evidence. Non-classical or emerging biomarkers include TLT-1, TREM-1/sTREM-1, angiopoietins (Ang-1/Ang-2), serotonin, ferritin, dengue virus envelope domain III (EIII), and soluble endothelial molecules such as IL-1RA, sCD163, SDC-1, sVCAM-1, IL-8, and IP-10. Alone or in combination, these markers can be used/explored as prognostic tools and/or as therapeutic targets. Finally, integrating multimarker panels encompassing hemostatic, inflammatory, and endothelial pathways may improve prognostic stratification. This approach could support targeted interventions and help reduce complications such as thrombocytopenia, plasma leakage, and dengue shock.
Exploration of the Key Mechanism by Which Kaempferol Inhibits Glycolysis in Hepatocellular Carcinoma Cells via the AKT-mTOR Pathway.
Xu H, Qian L, Cao Y … +6 more , Ou M, Ni Y, Zhang B, Chen L, Hao J, Wang Z
FASEB J · 2026 Jun · PMID 42322592 · Publisher ↗
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Kaempferol shows potential in suppressing HCC progression via glycolysis regulation, yet its molecular targets and mechanisms a...
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Kaempferol shows potential in suppressing HCC progression via glycolysis regulation, yet its molecular targets and mechanisms are unclear. Transcriptomic data were analyzed to identify HCC-related DEGs. Intersection with kaempferol's glycolysis-related targets yielded candidate genes. A prognostic risk model was constructed and validated by ROC curves and survival analysis. GSEA and single-cell RNA sequencing explored mechanisms and cellular heterogeneity. Mendelian randomization assessed causality between prognostic genes and HCC. After HCC cells were treated with different concentrations of kaempferol, the effects of kaempferol on proliferation, invasion, and migration of HCC cells were detected by CCK-8, cell clone formation, and Transwell cell scratch healing experiments. The expression levels of key proteins in the AKT-mTOR signaling pathway and glycolytic rate-limiting enzymes were detected by Western blot. The spectrophotometric method was used to detect the effect of kaempferol on glucose uptake and lactate production of HCC cells. Finally, the impact of knocking down CA9 on glucose uptake and lactic acid production in liver cancer cells was analyzed. The prognostic risk model identified GRK6, ABCC1, CA9, and CDK5R1 as prognostic genes. GSEA implicated cell cycle and PI3K-Akt pathways in HCC progression driven by these genes. Single-cell analysis revealed pronounced upregulation of prognostic genes in hepatocytes. Finally, MR analysis confirmed that CDK5R1 was a risk factor for the incidence of HCC. Kaempferol significantly inhibited the proliferation, invasion, and migration of MHCC97H and Huh7 cells, as well as the expression levels of PKM2, HK2, p-AKT, p-mTOR, and p-RPS6. Kaempferol significantly reduced glucose uptake and lactic acid production in MHCC97H and Huh7 cells. Knockdown of CA9 inhibited the uptake of glucose and lactic acid production, along with suppressing the expression of HK2 and PKM2 in MHCC97H and Huh7 cells. This study found that kaempferol targeted the AKT-mTOR pathway and downregulated the CA9 gene, thereby modulating glycolysis and ultimately suppressing the proliferation, invasion, and migration of hepatocellular carcinoma.
Correction to "PAI-1 Induction During Kidney Injury Promotes Fibrotic Epithelial Dysfunction via Deregulation of Klotho, p53, and TGF-β1-Receptor Signaling".
FASEB J · 2026 Jun · PMID 42322305 · Publisher ↗
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RETRACTION: Resistance to Chicken Amyloid Arthropathy Is Associated With a Dysfunctional Mutation in Serum Amyloid A.
FASEB J · 2026 Jun · PMID 42319694 · Publisher ↗
C. Falker-Gieske, N.-F. Paul, M. Spourita, J.D. Gilthorpe, K. Gustmann, and J. Tetens, "Resistance to Chicken Amyloid Arthropathy Is Associated With a Dysfunctional Mutation in Serum Amyloid A," The FASEB Journal 37, no....
C. Falker-Gieske, N.-F. Paul, M. Spourita, J.D. Gilthorpe, K. Gustmann, and J. Tetens, "Resistance to Chicken Amyloid Arthropathy Is Associated With a Dysfunctional Mutation in Serum Amyloid A," The FASEB Journal 37, no. 1 (2023): e22700, https://doi.org/10.1096/fj.202200359RR. The above article, published online on 14 December 2022 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the authors; the journal Editor-in-Chief, Loren E. Wold; and Wiley Periodicals LLC. The authors contacted the journal to request a correction, due to their discovery of a mutation in the plasmid used to generate the control LMH SAA.WT cell lines. This development led to the deletion of the C-terminal KY dipeptide and the addition of a 20 amino acid C-terminal neopeptide fusion with a different sequence than what was reported in the article. The SAA.R90S plasmid carried the correct sequence, but the perceived effects of the LMH SAA.R90S protein in cells were being compared with the incorrect control LMH SAA.WT plasmid. This error influenced the interpretation of some of the published results. The authors noted that this was an unintentional error. However, because the errors impact the study's premise and results, the article must be retracted. A revised version is forthcoming.
m6A-Modulated RNF14 Favors Fatty Acid Oxidation to Drive Colorectal Cancer Progression via Regulation of TAF1/PINK1 Axis.
Lv L, Lv F, Li B … +2 more , Li G, Yi H
FASEB J · 2026 Jun · PMID 42319387 · Publisher ↗
The contribution of fatty acid oxidation (FAO) to colorectal cancer (CRC) progression has been recognized. However, the detailed mechanisms underlying FAO remain obscure. This study explored the influence of ring finger...
The contribution of fatty acid oxidation (FAO) to colorectal cancer (CRC) progression has been recognized. However, the detailed mechanisms underlying FAO remain obscure. This study explored the influence of ring finger protein 14 (RNF14) on FAO and its related mechanisms in CRC. We found that RNF14 was up-regulated in CRC, which was positively associated with FAO level. High expression of RNF14 promoted FAO to facilitate growth of CRC cells in vitro and in vivo. Mechanistically, RNA binding motif protein 15 (RBM15)/YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated N6-methyladenosine (m6A) modification enhanced RNF14 translation. RNF14 reduced TATA-box binding protein associated factor 1 (TAF1) protein stability via promoting its ubiquitination. Moreover, TAF1 bound to PTEN-induced kinase 1 (PINK1) promoter to trigger its transcription. RNF14 knockdown or TAF1 overexpression repressed FAO of CRC cells, which was overturned by TAF1 or PINK1 silencing, respectively. In conclusion, RBM15/YTHDF1-mediated m6A modification of RNF14 mRNA contributed to FAO enhancement via ubiquitination of TAF1 to transcriptionally inhibit PINK1, thus promoting CRC progression.
Resveratrol Alleviates Neurogenic Bladder Fibrosis and Urothelial Pyroptosis by Inhibiting the AKT/mTOR Signaling Pathway.
Chen J, Wang R, Zhou X … +7 more , Ding Y, Tang H, Mi J, Long C, Shen L, Wei G, Wu S
FASEB J · 2026 Jun · PMID 42319380 · Publisher ↗
Neurogenic bladder (NB) is a debilitating urological disorder characterized by progressive bladder remodeling, fibrosis, and functional deterioration, yet effective mechanism-based therapies remain limited. The AKT/mTOR...
Neurogenic bladder (NB) is a debilitating urological disorder characterized by progressive bladder remodeling, fibrosis, and functional deterioration, yet effective mechanism-based therapies remain limited. The AKT/mTOR signaling pathway is a central regulator of cellular growth, inflammation, and tissue remodeling, but its contribution to NB pathogenesis remains incompletely understood. In this study, we established an NB rat model by bilateral L6-S1 spinal nerve transection and evaluated the therapeutic effects of resveratrol. Urodynamic and histological analyses showed that resveratrol reduced residual volume and pressure change, improved bladder compliance, attenuated bladder enlargement and fibrosis, and alleviated secondary renal injury. In addition, resveratrol partially restored β III Tubulin immunoreactivity and reduced pathological remodeling in both mucosal and muscular compartments of the bladder. Mechanistically, resveratrol suppressed epithelial-mesenchymal transition (EMT)-like changes, apoptosis, and pyroptosis, as reflected by restoration of E-cadherin, reduction of α-SMA, Bax, cleaved caspase-3, NLRP3, IL-1β, and Caspase-1, and decreased inflammatory cytokine production. These effects were accompanied by marked inhibition of AKT/mTOR/S6K signaling activation in vivo. Consistently, in vitro experiments showed that resveratrol protected urothelial cells from TGF-β1-induced injury, whereas pharmacological re-activation of mTOR with MHY1485 partially reversed its anti-fibrotic and anti-pyroptotic effects. Collectively, these findings indicate that resveratrol alleviates NB-associated bladder injury and fibrosis by inhibiting the AKT/mTOR/S6K signaling pathway, highlighting this pathway as a potential therapeutic target for NB.
Tmem67 Is Required for Spermiogenesis and Male Fertility in Mice.
Wang B, Ling S, Sun W … +11 more , Pan L, Zhang A, Ye C, Wang X, Wang H, Wang Z, Zhang P, Wu B, Liu M, Gao J, Wen Z
FASEB J · 2026 Jun · PMID 42313943 · Publisher ↗
Spermiogenesis dysfunction is a major cause of male infertility; however, the underlying molecular mechanisms involved remain incompletely elucidated. Although transmembrane protein 67 (TMEM67), a ciliary transition zone...
Spermiogenesis dysfunction is a major cause of male infertility; however, the underlying molecular mechanisms involved remain incompletely elucidated. Although transmembrane protein 67 (TMEM67), a ciliary transition zone protein implicated in ciliopathies, is highly enriched in mouse testes, its cell type-specific functional relevance in spermatogenesis is unclear. Here, we generated germ cell-specific (Stra8-Tmem67) and Sertoli cell-specific (Amh-Tmem67) Tmem67 knockout mice to investigate the function of TMEM67 in spermatogenesis and male fertility. Amh-Tmem67 mice maintained normal fertility and exhibited normal spermatogenesis, with no significant differences in testicular histology or sperm count, morphology, or motility compared with wild-type (WT) controls. However, Stra8-Tmem67 males were completely infertile, manifesting severe oligoasthenoteratozoospermia (OAT) characterized by a drastic reduction in sperm count, total loss of sperm motility, and global sperm malformation. Further investigations revealed that TMEM67 deletion did not impair spermatogonial proliferation or meiosis, but instead disrupted key spermiogenic events, including manchette dynamics, acrosome biogenesis, and flagellum development. Proteomic analysis indicated that TMEM67 knockout altered the expression of numerous spermiogenesis-related proteins. Furthermore, our experiments confirmed that TMEM67 deficiency led to profound perturbations in both the expression levels and subcellular localization of key spermiogenic regulators in the testis. Collectively, our findings demonstrate that TMEM67 is indispensable for spermiogenesis and male fertility, revealing its critical role in coordinating manchette function, axonemal integrity, and spermiogenesis-related protein regulation, providing novel insights into OAT pathogenesis.
Exercise Training Stimulates the Release of Glutathione Peroxidase 1 (GPX1)-Enriched Extracellular Vesicles That Promote Angiogenesis.
Fliflet AM, Spradlin RA, Tan Y … +21 more , Nishitha Vijayan A, Choi SJ, Kao WC, Aksamitiene E, Nelappana M, Ding S, Huang KY, Joshi A, Kambar N, Bludgen T, Meehan M, Boss JL, Knipp M, Fan H, Leal C, Sunde RA, Dobrucki LW, Boppart SA, Kong HJ, Sweedler JV, Boppart MD
FASEB J · 2026 Jun · PMID 42313915 · Full text
An acute bout of high intensity exercise can transiently increase circulating extracellular vesicles (EVs) that possess beneficial molecular cargo. However, no studies to date have comprehensively evaluated plasma quanti...
An acute bout of high intensity exercise can transiently increase circulating extracellular vesicles (EVs) that possess beneficial molecular cargo. However, no studies to date have comprehensively evaluated plasma quantity, protein content, and function of EVs collected from blood after multiple bouts of endurance exercise. Here we demonstrate that 4 weeks of voluntary wheel running increases plasma EV quantity when collected immediately after the last bout of training in mice. These EVs (ExerVs) are enriched in oxidoreductases, including the antioxidant glutathione peroxidase 1 (GPX1). Repeated, systemic injections of ExerVs into sedentary recipient mice twice per week for 4 weeks did not alter mitochondrial content or function, fiber size, or fiber type, but increased capillary density and perfusion in skeletal muscle. ExerVs also stimulated tube formation and branch lengthening in vitro and improved the recovery of capillary content after a period of disuse in vivo. ExerVs isolated from GPX1 mice lacked the ability to stimulate vessel formation, whereas GPX1-encapsulated liposomes robustly increased capillary growth, both in vitro and in vivo. The results from this study suggest that circulating ExerVs positively impact vascular structure and function in skeletal muscle in a manner that may be dependent on GPX1.
Epigenetic-Genetic Crosstalk at the Cancer-Diabetes Interface: Convergent Molecular Pathways, Multi-Omics Biomarkers, and Dual Therapeutic Targets.
Singh V, Shirbhate E, Johariya V … +4 more , Kore R, Veerasamy R, Tiwari AK, Rajak H
FASEB J · 2026 Jun · PMID 42313898 · Publisher ↗
The complex interdependence between cancer and diabetes has become a major subject of research in molecular medicine since multiple data points indicate that these two conditions have some molecular processes and regulat...
The complex interdependence between cancer and diabetes has become a major subject of research in molecular medicine since multiple data points indicate that these two conditions have some molecular processes and regulatory pathways in common. The complex relationship between epigenetic and genetic modifications linking these two prevalent diseases was explored in this comprehensive study. Molecular fingerprints such as abnormal DNA methylation, histone modifications, and non-coding RNA dysregulation have become known in recent times as a result of breakthroughs in the multi-omics technology. We systematically analyze the prevalent risk factors such as obesity, chronic inflammation, and oxidative stress that cause these two diseases through various yet similar biological processes. Particular emphasis is put on such important signaling pathways as insulin/IGF, PI3K/AKT/mTOR, and AMPK cascades that are fundamental in both diseases. We also provide an overview of new technologies that can enhance our knowledge of the molecular etiology of these diseases, such as single-cell sequencing and artificial intelligence. These observations are evaluated clinically from the perspective of biomarkers discovery, therapeutic targeting, and personalized medicine modalities. Lastly, we discuss future research for this study and future potential therapies based on the focus on similar biological pathways. This review offers insightful commentary on the field of cancer and diabetes intersection that can help to create more rational treatment regimens for both diseases.
Cryo-EM Structures of the Human 5-HTR Bound to Three Distinct Ligands Reveal Molecular Determinants of Subtype Selectivity.
Yang G, Zhong Y, Jiao H … +2 more , Tao Y, Guo Q
FASEB J · 2026 Jun · PMID 42313494 · Publisher ↗
The 5-HTR, a member of the G protein-coupled receptor (GPCR) family, has been implicated in various diseases, including cardiovascular conditions, fibrotic disorders, cancer, and neuropsychiatric illnesses. Despite its t...
The 5-HTR, a member of the G protein-coupled receptor (GPCR) family, has been implicated in various diseases, including cardiovascular conditions, fibrotic disorders, cancer, and neuropsychiatric illnesses. Despite its therapeutic potential, the 5-HTR remains largely underexplored due to the limited availability of subtype-selective ligands. Additionally, many drugs either exhibit off-target binding to 5-HTR or fail to achieve specificity for their intended receptor subtype. Here, we present three cryo-electron microscopy structures of the human 5-HTR in complex with the antagonist tegaserod, the inverse agonist ritanserin, and the selective antagonist RS127445, respectively. These structures reveal distinct binding modes for each ligand, and through detailed analysis, we identify residues L362 and V366 as key contributors to 5-HT subtype selectivity, while E363 and the ECL2 region play critical roles in 5-HTR subtype selectivity. Our findings offer valuable insights into the molecular mechanisms behind ligand selectivity for 5-HTR, laying the groundwork for the development of 5-HTR-selective ligands.
Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts.
Vrettou S, Zetzsche S, Wirth B
FASEB J · 2026 Jun · PMID 42301137 · Full text
Spinal muscular atrophy (SMA) is caused by loss of SMN protein and is increasingly recognized as a multisystem disorder involving molecular pathology beyond motor neurons. Recently, we identified dysregulated NRF2-KEAP1...
Spinal muscular atrophy (SMA) is caused by loss of SMN protein and is increasingly recognized as a multisystem disorder involving molecular pathology beyond motor neurons. Recently, we identified dysregulated NRF2-KEAP1 signaling in SMA mice. Since NRF2 coordinates transcriptional programs that maintain cellular redox homeostasis and adaptive stress responses, we investigated whether NRF2 signaling is similarly altered in fibroblasts derived from individuals with SMA type I and whether it can be pharmacologically engaged. Compared with control fibroblasts, SMA fibroblasts displayed reduced basal expression of NRF2 target proteins, including NQO1 and xCT (SLC7A11), along with decreased levels of PGC1α. Omaveloxolone (OMAV), a pharmacological NRF2 activator approved for the treatment of Friedreich's ataxia, increased cell viability and upregulated NRF2 target proteins in both control and SMA fibroblasts. Notably, OMAV produced a modest increase in SMN protein abundance and PGC1α levels selectively in SMA cells. Together, these findings support diminished NRF2 pathway activity as a feature of SMA fibroblasts and demonstrate that OMAV activates NRF2 signaling in this human SMA cellular model, consistent with enhanced cytoprotective signaling. These results support further investigation of NRF2 activation, including OMAV, as a potential adjunctive strategy in SMA.
Dietary High Fiber and N-Carbamylglutamate Enhance Sow Reproductive Performance via Modulating Lactobacilli, Lipid Metabolites, and the PI3K-Akt Signaling Pathway.
Wang H, Liang Y, Wang Z … +8 more , Zhang Y, Tu W, Zhou J, Diao Y, Pei H, Huang J, Zhou X, Tan Y
FASEB J · 2026 Jun · PMID 42301089 · Publisher ↗
The aim of this study was to investigate the combined effects of a high-fiber diet supplemented with N-carbamylglutamate (NCG) (H + N) on the gut microbiota, metabolites, and transcriptome in Landrace × Yorkshire sows us...
The aim of this study was to investigate the combined effects of a high-fiber diet supplemented with N-carbamylglutamate (NCG) (H + N) on the gut microbiota, metabolites, and transcriptome in Landrace × Yorkshire sows using a multi-omics approach. Sows were allocated to four groups in a 2 × 2 design: Low-fiber or high-fiber diets, each with or without 0.05% NCG supplementation. The H + N treatment significantly increased litter weight at weaning. Metagenomic analysis revealed H + N significantly altered gut microbiota composition and function, particularly enriching Lactobacillus at multiple taxonomic levels from order to species (including Lactobacillus sp. 910 589 175). Plasma metabolomics identified two key lipid mediators, L-α-glycerylphosphorylcholine and taurocholic acid, whose abundances were significantly elevated by H + N and positively correlated with the enriched Lactobacillus. Transcriptomic profiling showed activation of the PI3K-Akt signaling pathway in response to H + N, which was associated with observed improvement in litter weight at weaning. Collectively, the multi-omics study uncovered a novel synergistic axis wherein H + N modulated the gut microbiome (specifically Lactobacillus enrichment), which in turn shaped the lipid metabolome to activate the PI3K-Akt pathway, ultimately enhancing sow reproductive efficiency.
Vitamin D-VDR Signaling Modulates Epithelial-Driven Intra-Alveolar Coagulation via NF-κB in Sepsis-Associated ARDS.
Dong Q, Cheng Y, Yuan J … +7 more , Xiao C, Chen X, Tao J, Wang Y, Wang J, Tian J, Shen F
FASEB J · 2026 Jun · PMID 42300107 · Publisher ↗
Sepsis-associated acute respiratory distress syndrome (ARDS) is characterized by excessive inflammation and dysregulated intra-alveolar coagulation, leading to fibrin deposition and impaired alveolar function. The regula...
Sepsis-associated acute respiratory distress syndrome (ARDS) is characterized by excessive inflammation and dysregulated intra-alveolar coagulation, leading to fibrin deposition and impaired alveolar function. The regulatory role of vitamin D-vitamin D receptor (VDR) signaling in epithelial coagulation responses remains incompletely defined. We investigated the role of vitamin D-VDR signaling in regulating epithelial-driven intra-alveolar coagulation in sepsis-associated lung injury using vitamin D-deficient mice, LPS-induced acute lung injury models, RLE-6TN alveolar epithelial cells, and clinical samples from patients with ARDS. Expression of VDR, NF-κB p65, tissue factor (TF), and plasminogen activator inhibitor-1 (PAI-1) was assessed using qRT-PCR, Western blotting, ELISA, and immunohistochemistry. Functional experiments included 1,25(OH)D supplementation, VDR silencing, and NF-κB p65 gain- and loss-of-function approaches. Vitamin D deficiency significantly exacerbated LPS-induced lung injury, pulmonary edema, and intra-alveolar hypercoagulation, as reflected by increased TF and PAI-1 expression in lung tissue and bronchoalveolar lavage fluid. LPS challenge suppressed VDR expression and concurrently activated NF-κB signaling In Vivo and in alveolar epithelial cells. Supplementation with 1,25(OH)D restored VDR expression and attenuated TF and PAI-1 induction. Conversely, VDR silencing enhanced NF-κB p65 activation and amplified epithelial procoagulant responses. Mechanistically, NF-κB p65 was required for TF and PAI-1 upregulation, and its overexpression abolished the inhibitory effects of vitamin D-VDR signaling. Clinically, patients with ARDS exhibited reduced circulating 25(OH)D levels and decreased VDR expression compared with healthy controls. Vitamin D-VDR signaling acts as an endogenous protective axis that restrains NF-κB-driven epithelial procoagulant activation in sepsis-associated ARDS. Disruption of this pathway promotes TF- and PAI-1-mediated intra-alveolar coagulation, suggesting that restoration of vitamin D-VDR signaling may represent a potential adjunctive therapeutic strategy for ARDS.
Reduced Mechanical Tactile Stimulation Under Space Microgravity Affects Synaptic Signaling and Contributes to Neuromuscular Aging in Caenorhabditis elegans.
Higashitani A, Moon JH, Hwang JI … +14 more , Higashitani N, Hashizume T, Abu AA, Ooizumi K, Sazuka I, Hashizume Y, Umehara M, Alcantara AV, Kim BS, Etheridge T, Szewczyk NJ, Abe T, Lee JI, Higashibata A
FASEB J · 2026 Jun · PMID 42300093 · Full text
Although space travel is becoming more accessible, our understanding of how the space environment and microgravity (μG) affect biology, physiology, and human health remains incomplete. This study examined the effects of...
Although space travel is becoming more accessible, our understanding of how the space environment and microgravity (μG) affect biology, physiology, and human health remains incomplete. This study examined the effects of μG on synaptic signaling and neuromuscular aging in Caenorhabditis elegans. The D01 cohort, consisting of L4 larvae to young adults raised in μG, exhibited a downregulation of genes linked to synaptic signaling, dopamine response, locomotion, cuticle development, and mitochondrial metabolism. This was accompanied by altered synapse dynamics, reduced motility, and shorter body length. In μG, aged worms showed a reduction in collagen gene expression, increased abnormalities in motor neuron morphology, changes in synaptic vesicle dynamics, and a collapse of mitochondrial morphology in body wall muscles, highlighting exacerbated aging-like phenotypes. The gentle-touch mechanoreceptor MEC-4 was identified as a key mediator of μG-induced body length reduction and changes in extracellular matrix gene expression. mec-4 mutants did not show μG-associated body shortening. The expression of most mechanoreceptor genes, including stretch-activated channels unc-105 and del-1, was downregulated under μG conditions. Notably, the expression of tmc-1 and degt-1 mechanoreceptor genes was downregulated independently of MEC-4. Restoration of physical stimulation using culture medium with small beads in space mitigated many μG-induced neuromuscular defects and expression alterations including those in mechanoreceptor genes. These results highlight the role of mechanical stimuli in maintaining neuromuscular integrity during spaceflight and suggest that restoring tactile input could counter health risks from reduced tactile stimulation during long-term space missions.
The Caspase-1/GSDMD/PXN/VCAM-1 Cascade Mediates Cerebral Ischemia-Reperfusion Injury.
Zhang T, Han S, Zhang Y … +11 more , Li W, Yang H, Wang Y, Liu Y, Fan X, Yang S, Wang M, Pu T, Wang G, Wang D, Wang G
FASEB J · 2026 Jun · PMID 42300005 · Publisher ↗
Pyroptosis, as an inflammatory type of regulated cell death, is associated with the pathogenesis of various inflammatory diseases. Targeted therapy for pyroptosis has shown promise in multiple preclinical models of neuro...
Pyroptosis, as an inflammatory type of regulated cell death, is associated with the pathogenesis of various inflammatory diseases. Targeted therapy for pyroptosis has shown promise in multiple preclinical models of neurological injury and disorders. Stroke is one of the leading causes of morbidity and mortality worldwide and the top cause of disease-related death in China. Although the pyroptosis signaling pathway has been studied in cerebral ischemic diseases, its pathophysiological mechanisms in brain microvascular endothelial cells (BMECs) remain unclear. In this study, we demonstrate that pyroptosis levels in BMECs are significantly elevated under ischemia-reperfusion (I/R) conditions and are closely associated with extensive macrophage infiltration in the brain, leading to inflammatory injury. We observed that the caspase-1 signaling pathway mediates GSDMD-dependent VCAM-1 expression, promoting the adhesive interaction between reactive endothelial cells and macrophages, thereby exacerbating the inflammatory microenvironment in the brain. Furthermore, omics analysis revealed that, upon caspase-1 activation, phosphorylated PXN (p-PXN) facilitates VCAM-1-mediated adhesion upstream, amplifying the inflammatory cascade and aggravating cerebral ischemic injury. In summary, our findings highlight the potential of non-glial and non-neuronal cells in amplifying neuroinflammation, providing additional theoretical support for the treatment of ischemic brain injury.
Salvianolic Acid B Protects Against Contrast-Induced Acute Kidney Injury by Attenuating Ferroptosis via the SIRT1/Nrf2 Pathway.
Yuan H, Shi X, Qin J … +9 more , Wang Y, Yuan Y, Zhang Y, Wang Y, Zhang C, Zhu J, Chen L, Xie S, Shen W
FASEB J · 2026 Jun · PMID 42299992 · Publisher ↗
Contrast-induced acute kidney injury (CI-AKI) poses a significant clinical challenge and contributes to a considerable healthcare burden. Ferroptosis has been increasingly recognized as an important mechanism of renal tu...
Contrast-induced acute kidney injury (CI-AKI) poses a significant clinical challenge and contributes to a considerable healthcare burden. Ferroptosis has been increasingly recognized as an important mechanism of renal tubular epithelial cell injury in CI-AKI. Salvianolic acid B (SalB), a natural compound with anti-inflammatory and antioxidant properties, has shown protective effects in various kidney diseases. However, its role in CI-AKI-associated ferroptosis has not been fully clarified. In this study, we established a rat model of CI-AKI by subcutaneous injection of carbon tetrachloride for 6 weeks followed by iopamidol administration, and an in vitro model using iopamidol-treated HK-2 cells. Effects of tubular injury and ferroptosis were examined both in vivo and in vitro. Cycloheximide chase assay, cellular thermal shift assay, and molecular docking were used to assess the binding capacity of SalB to SIRT1. Our results showed that SalB significantly alleviated renal injury, reduced iron accumulation, oxidative stress levels, and lipid peroxidation, upregulated the expression of SLC7A11 and GPX4, and downregulated ACSL4 expression in both iopamidol-treated rat kidneys and HK-2 cells. Mechanistically, SalB targeted and bound to SIRT1, enhancing its stability, thereby promoting Nrf2 upregulation and nuclear translocation, which in turn enhanced the expression of SLC7A11 and GPX4 and attenuated ferroptosis. Silencing either SIRT1 or Nrf2 in HK-2 cells partially abrogated the protective effect of SalB. Collectively, our results support SalB as a viable treatment strategy for CI-AKI.
DNA From Neutrophil Extracellular Traps Restricts Group 3 Innate Lymphoid Cells Function in Intestinal Epithelial Repair via CCDC25.
Xu B, Ke X, Xie X … +12 more , Yi Q, Li C, Zhao M, Deng X, Wang Q, Chen H, Xu R, Cao S, Zhu Y, Zhou L, Wang Q, Luo X
FASEB J · 2026 Jun · PMID 42299911 · Full text
Accumulation of neutrophil extracellular traps (NETs) in ulcerative colitis (UC) is associated with impaired intestinal epithelial barrier integrity. However, little is known about how NETs affect intestinal epithelial r...
Accumulation of neutrophil extracellular traps (NETs) in ulcerative colitis (UC) is associated with impaired intestinal epithelial barrier integrity. However, little is known about how NETs affect intestinal epithelial repair. This study sheds light on the molecular mechanisms through which excess NETs cause intestinal epithelial damage in UC mice. We found that UC mice had elevated levels of circulating cell-free DNA (cfDNA), mainly from NET byproducts (e.g., NET-DNA). NET-DNA in the intestine worsened UC symptoms, while DNase I treatment to eliminate it alleviated these symptoms. RNA-seq analysis revealed significant changes in IL-22 mRNA between wild-type and peptidylarginine deiminase 4 knockout (PAD4) mice. Flow cytometry results indicated that NET-DNA mainly affected IL-22 secretion by group 3 innate lymphoid cells (ILC3s), while other forms of DNA had little influence on IL-22 expression. The IL-22ILC3s ratio was restored in both DNase I-treated and PAD4 mice; moreover, levels of mucin, tight junction proteins, and Ki67 were significantly increased. Co-incubating ILC3s or the mouse lymphocyte cell line MNK3 with NET-DNA decreased IL-22 levels. ILC3s expressed the NET-DNA receptor coiled-coil domain containing protein 25 (CCDC25); however, NET-DNA did not affect IL-22 secretion in shCCDC25-MNK3 cells. Additionally, inhibiting ILK-HIF-1α proteins, downstream of CCDC25, increased IL-22 production in MNK3 cells. Finally, we established an in vitro culture system using MNK3 and Caco-2 cells. The supernatant from NET-DNA-treated MNK3 cells increased FITC-dextran permeability and reduced ZO-1 expression in Caco-2 cells. Thus, CCDC25 in ILC3s responds to NET-DNA by reducing IL-22 levels in UC mice, negatively impacting mucosal healing.
Epithelial and Interstitial Gli2 Activation Correlates With Renal Tubulointerstitial Fibrosis and Facilitates FoxM1-Associated Myofibroblast Phenotypic Transition.
Yuan Z, Sun Y, Kong L … +8 more , Yu S, Zheng F, Yan P, Liu B, He D, Zuo Y, Lu H, Bai Y
FASEB J · 2026 Jun · PMID 42295123 · Publisher ↗
Abnormal activation of Hedgehog signaling is involved in renal fibrogenesis, a key process in chronic kidney disease (CKD) progression. However, the isoform-specific roles of Gli transcription factors remain unclear. Thi...
Abnormal activation of Hedgehog signaling is involved in renal fibrogenesis, a key process in chronic kidney disease (CKD) progression. However, the isoform-specific roles of Gli transcription factors remain unclear. This study aimed to elucidate the contribution of Gli2 to renal fibrosis. Multiple murine models of renal fibrosis-unilateral ureteral obstruction, ischemia-reperfusion injury, and aristolochic acid nephropathy-were employed, alongside human CKD specimens. In vitro assays, including genetic silencing, overexpression, co-immunoprecipitation, immunofluorescence, promoter analysis, F-actin staining, and TGF-β/SB431542 intervention assays were used to evaluate Gli2 function and its interaction with FoxM1. This study identifies Gli2, but not Gli1 or Gli3, as the primary Hedgehog signaling mediator in fibrotic kidneys, showing its activation in both epithelial and interstitial compartments. TGF-β-induced Gli2 activation promoted fibrogenesis via tubular epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast differentiation (FMD), and cytoskeletal remodeling. FoxM1 is a potential dowgnstream candidate transcriptionally regulated by Gli2, with two conserved Gli-binding sites within its promoter. FoxM1 knockdown partially mitigated Gli2-driven fibrotic effects. Pharmacological Gli2 suppression with GANT61 alleviated fibrotic injury in the UUO mouse model. In conclusion, activated Gli2 is closely associated with renal tubulointerstitial fibrosis and may facilitate fibrogenesis in a FoxM1-relevant regulatory pattern. The TGF-β/Hedgehog/Gli2/FoxM1 axis represents a promising therapeutic target for combating progressive CKD.
CircCOL3A1 Drives Trophoblast Ferroptosis Through TIAL1-p53 Axis to Promote Preeclampsia Progression.
Wang H, Yin L, Zheng H … +2 more , Shi Z, Zhao C
FASEB J · 2026 Jun · PMID 42295051 · Publisher ↗
Preeclampsia (PE) is a major pregnancy-specific disorder driven by impaired trophoblast function, placental hypoxia, and excessive oxidative stress. Ferroptosis has recently emerged as a key contributor to placental path...
Preeclampsia (PE) is a major pregnancy-specific disorder driven by impaired trophoblast function, placental hypoxia, and excessive oxidative stress. Ferroptosis has recently emerged as a key contributor to placental pathology; however, the upstream regulatory mechanisms that activate ferroptosis in trophoblasts remain incompletely defined. Circular RNAs (circRNAs) have been implicated in trophoblast dysfunction, yet the ferroptosis-related circRNA network in PE is largely unexplored. This study investigated whether circCOL3A1 regulates p53-mediated ferroptosis in trophoblasts and contributes to PE pathogenesis. CircCOL3A1 expression was examined in placental tissues and HTR-8/SVneo cells. Hypoxia and hypoxia/reoxygenation models were used to mimic PE-associated stress in vitro. Loss- and gain-of-function assays, ferroptosis measurements, RNA pull-down, RIP, FISH, and Actinomycin-D stability analyses were performed to elucidate the circCOL3A1/TIAL1/p53 axis. A reduced uterine perfusion pressure (RUPP) rat model was used to evaluate the in vivo effects of circCOL3A1 knockdown. CircCOL3A1 was significantly elevated in PE placentas and hypoxia-treated trophoblasts, exhibiting cytoplasmic localization and high structural stability. CircCOL3A1 knockdown restored trophoblast migration, invasion, viability, and reduced apoptosis under hypoxia. Silencing circCOL3A1 suppressed hypoxia-induced ferroptosis by reducing ROS, MDA, and iron levels while restoring GSH and GPX4. Mechanistically, circCOL3A1 bound the RNA-binding protein TIAL1 to enhance p53 mRNA stability, thereby promoting p53-dependent ferroptosis. In vivo, circCOL3A1 silencing lowered maternal blood pressure and proteinuria, reduced placental ferroptosis, and improved fetal survival in PE rats. CircCOL3A1 drives trophoblast ferroptosis through a TIAL1-dependent stabilization of p53, contributing to PE progression. Targeting the circCOL3A1/TIAL1/p53 axis may offer a promising therapeutic strategy for preeclampsia.
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