FASEB Journal[JOURNAL]
Sun
200 papers
ODC1-Mediated Ornithine Metabolism Exacerbates Obesity by Disrupting AMPK/ACC Pathway.
Wang S, Huo K, Liu S … +7 more , Qiao M, Zhao N, Sun D, Duan J, Lu C, Liang L, Cao G
FASEB J · 2026 Jul · PMID 42381483 · Publisher ↗
Ornithine (OR) is a key intermediate metabolite; however, its molecular role in obesity remains unclear. This study aimed to investigate the effects of OR and its rate-limiting enzyme, ornithine decarboxylase 1 (ODC1), o...
Ornithine (OR) is a key intermediate metabolite; however, its molecular role in obesity remains unclear. This study aimed to investigate the effects of OR and its rate-limiting enzyme, ornithine decarboxylase 1 (ODC1), on lipid metabolism using high-fat diet (HFD)-induced obese C57BL/6 mice and C3H10T1/2 cell models. The results showed that OR supplementation and ODC1 overexpression exerted similar effects, including significantly aggravated HFD-induced obesity, elevated serum polyamine levels, impaired glucose tolerance, reduced oxygen consumption, and hepatic steatosis. Transcriptomic analysis combined with protein validation indicated that ODC1-promoted lipid deposition is associated with suppression of the AMPK/ACC pathway. In vitro, ODC1 overexpression promoted adipocyte proliferation and differentiation, accompanied by elevated levels of polyamines, including putrescine, spermidine, and spermine. Increased polyamine turnover further induced polyamine catabolic enzymes spermidine/spermine N1-acetyltransferase 1 (SAT1) and polyamine oxidase (PAOX), resulting in increased reactive oxygen species (ROS) accumulation, lipid peroxidation, and mitochondrial dysfunction. These changes were associated with suppression of the AMPK/ACC pathway, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, treatment with the ODC1 inhibitor DFMO or knockdown ODC1 markedly alleviated oxidative stress and lipid accumulation. Furthermore, OR supplementation failed to reverse oxidative stress and adipogenesis following ODC1 knockdown, indicating that its metabolic effects are largely dependent on ODC1 activity. Taken together, our findings reveal that ODC1-mediated polyamine synthesis links SAT1/PAOX-associated ROS production to AMPK/ACC and increased lipid accumulation, highlighting ODC1 as a potential therapeutic target for obesity and lipid metabolic disorders.
Targeting YAP1-Mediated Tubular Cell Senescence to Attenuate Maladaptive Repair and Fibrotic Transition After Acute Kidney Injury.
Zhao Z, An H, Sang Y … +5 more , Chen S, Zhou J, Zhang T, Li J, Zhou X
FASEB J · 2026 Jul · PMID 42381472 · Full text
Maladaptive repair following acute kidney injury (AKI) is an independent risk factor for the progression to chronic kidney disease (CKD). We hypothesize that renal tubular cell senescence and subsequent epithelial-mesenc...
Maladaptive repair following acute kidney injury (AKI) is an independent risk factor for the progression to chronic kidney disease (CKD). We hypothesize that renal tubular cell senescence and subsequent epithelial-mesenchymal transition drive maladaptive repair after AKI, ultimately leading to chronic renal fibrosis. We re-analyzed single-cell RNA sequencing data (ScRNA-seq, GSE212273) from kidney tissues post-IRI. In vivo, we employed unilateral IRI and folic acid models to simulate the AKI to CKD transition. Senolytics or verteporfin were given from Day 3 post-modeling. In vitro, human renal tubular epithelial (HK-2) cells were exposed to hydrogen peroxide or TGF-β. Sustained YAP1 overexpression promoted fibroblast activation and a profibrotic phenotypic shift. AKI induced a sustained increase in YAP1 expression, which was associated with tubular cell senescence and renal interstitial fibrosis. Senolytics effectively suppressed YAP1 activity, renal senescence, and alleviated kidney fibrosis. In vitro, persistent oxidative stress upregulated YAP1 expression and induced cell senescence. Knockdown of YAP1 downregulated Hippo signaling pathway, extracellular matrix reorganization, and reduced cell senescence. Conversely, YAP1 overexpression reversed the anti-senescence effect of senolytics. Finally, pharmacological inhibition of YAP1/TEAD1 attenuated cell senescence and post-ischemic renal fibrosis. Our findings indicate that sustained YAP1 overexpression mediates tubular cell senescence, which drives maladaptive kidney repair and facilitates the AKI to CKD transition. Senolytics or verteporfin therapy initiated after the peak of AKI offers a dual benefit: it protects the regenerative capacity of tubular cells and concurrently inhibits YAP1-driven epithelial-mesenchymal transition, thereby mitigating the progression of renal fibrosis.
Vancomycin Protects Against Lung Injury and Promotes Butyrate Metabolism.
Chen J, Su S, Zhang X … +7 more , Xiong F, Zheng H, Zhang W, Shen Y, Lin P, Gao H, Li Y
FASEB J · 2026 Jul · PMID 42366893 · Full text
Lung injury is one of the most common clinical respiratory diseases, caused by the exposure of lung tissue to various stimuli (including hypoxia, ischemia-reperfusion, and foreign substances). Among them, chronic lung in...
Lung injury is one of the most common clinical respiratory diseases, caused by the exposure of lung tissue to various stimuli (including hypoxia, ischemia-reperfusion, and foreign substances). Among them, chronic lung injury is characterized by continuous inflammation in the lungs, which damages the endothelial and epithelial cell barriers within the lungs. Clinically, it presents as severe hypoxia and diffuse functional impairment, and on imaging, it shows diffuse alveolar damage, accompanied by varying degrees of inflammation and airway obstruction. Several studies have highlighted the role of gut microbiota in modulating immune responses and pathological features of respiratory diseases through the gut-lung axis. However, the precise metabolic mechanism remains unknown. A lung injury model was generated by transplanting microbiota from acute lung injury (ALI) patients into healthy C57BL/6J mice. The changes in the gut microbiota and metabolic phenotypes of the feces samples from ALI patients and lung-injured mice were analyzed using 16S rRNA sequencing technology and metabolomics based on H-nuclear magnetic resonance (H-NMR), respectively. The effect of gut microbiota on lung injury was also explored after giving an oral vancomycin treatment to lung-injury mice. The data presented here show that Firmicutes formed the vital species of microbiota that was different in lung-injury mice. Moreover, butyrate (produced by Firmicutes) was the most crucial metabolite in the feces samples of ALI patients and lung-injury mice. ELISA and Hematoxylin-Eosin results showed aggravated functional disturbances in the intestinal barrier of ALI patients and lung inflammation in the lung-injured mice. These phenomena were significantly alleviated after the oral administration of vancomycin. Besides, the utilization of butyrate in the colon of mice was increased considerably. Thus, vancomycin can affect the metabolism of butyrate in the colon by influencing the intestinal microbiota, and it can help in the treatment of lung injury.
Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.
Goldstick J, Compte D, Sun CL … +2 more , Ritter AE, Crowder CM
FASEB J · 2026 Jul · PMID 42366871 · Full text
Hypoxia induces mitochondrial fragmentation. Whether this fragmentation promotes or prevents cell death and whether the mitochondrial dynamics machinery plays a role are unresolved. To address these questions, we measure...
Hypoxia induces mitochondrial fragmentation. Whether this fragmentation promotes or prevents cell death and whether the mitochondrial dynamics machinery plays a role are unresolved. To address these questions, we measured the effect of hypoxia on mitochondrial morphology in a Caenorhabditis elegans Raptor mutant resistant to hypoxic death and in mutants with disrupted mitochondrial fission and fusion. The Raptor loss-of-function mutant reduced hypoxia-induced mitochondrial fragmentation and death. However, forcing mitochondrial fragmentation prior to hypoxia by combining the Raptor mutation with a loss-of-function mutation in mitofusin did not increase hypoxic death. A loss-of-function mutation in drp-1, which is required for mitochondrial fission, did not block hypoxia-induced mitochondrial fragmentation nor enhance Raptor hypoxia resistance; rather, drp-1(lf) was surprisingly mildly hypoxia resistant and partially suppressed the high-level hypoxia resistance of the Raptor mutant. Likewise, loss of DRP-1 function interacted synthetically with the Raptor(lf) mutant to produce tangled mitochondria, demonstrating a role of Raptor in maintenance of the mitochondrial network. Vitamin B12 supplementation and feeding with a bacterial strain replete in vitamin B12 mitigated hypoxia-induced mitochondrial fragmentation. Our results demonstrate that fragmented mitochondria do not necessarily promote hypoxic cell death, and hypoxia-induced mitochondrial fragmentation is mechanistically distinct from physiological mitochondrial fission.
SENP3 Deficiency Inhibits Atherosclerosis by Regulating TLR4/NF-κB and SOAT2.
Zhou Z, Jiang T, Tang X … +12 more , Tang H, Han T, Gu J, Zhang S, Ren C, Shi Z, Fu W, Yu F, Li M, Lin C, Tai Z, Guo D
FASEB J · 2026 Jul · PMID 42366857 · Publisher ↗
SUMOylation plays critical roles in both initiation and development of atherosclerosis. SUMO-specific protease 3 (SENP3), a SUMO-specific protease that targets SUMO2/3 for deSUMOylation, is involved in vascular remodelin...
SUMOylation plays critical roles in both initiation and development of atherosclerosis. SUMO-specific protease 3 (SENP3), a SUMO-specific protease that targets SUMO2/3 for deSUMOylation, is involved in vascular remodeling and the modulation of macrophage functions. Here, we probed for the role of SENP3 in macrophages in the development of atherosclerosis. Stable and unstable plaques were collected from patients with atherosclerosis. A macrophage-specific SENP3 knockout mouse (Senp3) was generated and performed for a murine atherosclerosis model. Transcriptional sequencing was performed to identify potential mechanisms. SENP3 expression in macrophages was increased in unstable plaques, compared to stable plaques. The mean fluorescence intensity of SENP3 in macrophages infiltrating carotid plaques was positively correlated with circulating pro-inflammatory cytokines, low density lipoprotein (LDL-C), and triglycerides in atherosclerosis patients. Senp3 mice exhibited a markedly reduced atherosclerotic plaque area in the aorta, compared to wild-type mice. Knockdown of SENP3 in macrophages resulted in decreased secretion of pro-inflammatory cytokines, increased secretion of anti-inflammatory factors, and reduced foam cell formation. Transcriptional analysis identified significant enrichment in Toll-like receptor (TLR4) signaling pathway modulated by SENP3. Genetic deletion of either TLR4 (Tlr4) or Sterol O-Acyltransferase 2 (SOAT2) (Soat2) attenuated the exacerbation of atherosclerosis development induced by SENP3 overexpression. Furthermore, SENP3 regulated TLR4 and SOAT2 expression indirectly via the transcription factor MYC rather than through direct deSUMOylation of TLR4 or SOAT2 themselves. Downregulation of SENP3 in macrophages suppresses pro-inflammatory cytokine release by inhibiting TLR4 signaling and reduces foam cell formation by impeding SOAT2 expression, both mediated by the transcription factor MYC, thereby attenuating the development of atherosclerosis. Hence, SENP3 may represent a potential therapeutic target in atherosclerosis.
A Novel lncRNA-ADAT1/miR-449a-5p/FZD5 Axis Regulates Melanogenesis and Proliferation in Goat Melanocytes.
Liu J, Li Y, Tian W … +9 more , Tang Y, Tan J, Zhang X, Liang C, Wu J, Wang J, Xue L, Zhang Y, Ji K
FASEB J · 2026 Jul · PMID 42363863 · Publisher ↗
Long noncoding RNAs (lncRNAs) regulate diverse biological processes. However, their roles in melanogenesis remain poorly understood. This study investigated a lncRNA (ENSCHIT00000005207; lncRNA-ADAT1) that is differentia...
Long noncoding RNAs (lncRNAs) regulate diverse biological processes. However, their roles in melanogenesis remain poorly understood. This study investigated a lncRNA (ENSCHIT00000005207; lncRNA-ADAT1) that is differentially expressed in the skin of white and brown goats. lncRNA-ADAT1 expression in goat melanocytes was determined using quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. LncRNA-ADAT1 interference and overexpression vectors were designed, synthesized, and transfected into melanocytes. Target miRNAs of lncRNA-ADAT1 were predicted using bioinformatics tools, and their interactions were validated through luciferase reporter assays. MiRNA expression vectors were constructed and transfected into melanocytes, and the targeted regulatory gene was identified using a luciferase assay. The effects of target gene on melanogenesis and cell proliferation were investigated. qRT-PCR results revealed distinct expression patterns of lncRNA-ADAT1 in male and female goat tissues, whereas in situ hybridization assays showed that lncRNA-ADAT1 was abundantly expressed in melanocyte cytoplasm but minimally expressed in the nucleus. LncRNA-ADAT1 overexpression in melanocytes significantly increased (p < 0.01) melanogenesis and cell proliferation by interacting with miR-449a-5p as a competing endogenous RNA (ceRNA). MiR-449a-5p overexpression in melanocytes significantly inhibited (p < 0.01) melanin production and significantly promoted cell proliferation (p < 0.05). Furthermore, FZD5 had miR-449a-5p binding sites, and miR-449a-5p overexpression significantly reduced FZD5 expression (p < 0.001). Transfection of melanocytes with the FZD5 confirmed that FZD5 significantly increased (p < 0.01) melanin production and (p < 0.05) melanocyte proliferation by regulating β-Catenin expression. lncRNA-ADAT1 promoted melanogenesis and cell proliferation in goat melanocytes via the miR-449a-5p/FZD5/β-Catenin axis.
FMRP-Mediated Proteasome Regulation: A Novel Mechanism in ALS Pathology.
Majumder P, Ahsan A, Bubphachat P … +3 more , Akter K, Huang JK, Huang CS
FASEB J · 2026 Jul · PMID 42363684 · Publisher ↗
Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the hallmark cytoplasmic accumulation and aggregation of TAR DNA binding protein 43 (TDP-43), which impairs proteasome ac...
Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the hallmark cytoplasmic accumulation and aggregation of TAR DNA binding protein 43 (TDP-43), which impairs proteasome activity through its interaction with Tankyrase (TNKS). Using molecular and imaging techniques, we have identified a novel role for the Fragile X Mental Retardation Protein (FMRP) in regulating the TNKS/PI31-mediated proteasome activation mechanism in co-operation with TDP-43. Our results demonstrate that depletion of FMRP causes nuclear translocation of TDP-43, reducing cytoplasmic TNKS/TDP-43 co-localization, thereby releasing TNKS in the cytoplasm. Free TNKS gets associated with proteasome inhibitor of 31 kDa (PI31), reversing PI31-mediated inhibition of proteasome assembly, trafficking, and activity. Thus, FMRP regulates proteasome activity by modulating the subcellular distribution of TDP-43. Interestingly, FMRP expression is elevated in specific brain regions and spinal cords of TDP-43 transgenic ALS mice that helps more TDP-43 to stay in cytoplasm to sequester more TNKS with it, resulting in proteasome dysfunction in ALS disease system. We have demonstrated for the first time that FMRP can act as a disease modifier for ALS. ALS patients with high FMRP expression in the brain and spinal cord may exhibit more severe protein aggregation due to proteasome dysfunction.
Irisin Pretreatment Reveals Enhanced Protective Response Upon Hematopoietic Reconstitution in the Acquired Aplastic Anemia Mouse Model.
Li H, Kong D, Liu X … +14 more , Li X, Zhao Y, Wang Y, Li S, Hu J, Chen Y, Jiang Y, Wang F, Han Y, Shan N, Xu D, Tang D, Zhang L, Zheng C
FASEB J · 2026 Jul · PMID 42363679 · Publisher ↗
Acquired aplastic anemia (AA) is a prevalent nonmalignant hematologic disorder characterized by primary bone marrow failure (BMF), ineffective hematopoiesis, and consequent pancytopenia associated with abnormal immune re...
Acquired aplastic anemia (AA) is a prevalent nonmalignant hematologic disorder characterized by primary bone marrow failure (BMF), ineffective hematopoiesis, and consequent pancytopenia associated with abnormal immune responses and autoreactive T lymphocyte-mediated dysfunction of hematopoietic stem and progenitor cells (HSPCs). Recently, we observed a remarkable decrease in serum irisin levels in patients with AA, as well as beneficial effects of irisin administration on HSPC stemness and pancytopenia-related dysimmunity during BMF; however, the optimal protective effect of irisin on AA remains unknown. For this purpose, we further dissected the potential relationship between low irisin concentration and key T-cell subsets in patients and systematically compared the therapeutic effects of irisin pretreatment and irisin treatment in an AA mouse model using multifaceted analyses (e.g., body condition, peripheral blood cell counts, conventional staining, inflammatory cytokine detection, cell viability analysis of HSPCs, and T-cell subset analysis). Consistent with the decline in irisin concentration in AA, we further verified correlations with the indicated T-cell subsets. Using our well-established disease model, we found that AA mice with irisin pretreatment (Days -1 to 27) showed enhanced protective effects over those with irisin treatment (Days 7-27), including improved body condition and peripheral blood cell counts, reduced proinflammatory cytokines, rescue of HSPC stemness, and pancytopenia-related T-cell imbalance. Collectively, our data indicated the superiority of irisin pretreatment in alleviating AA-associated autoreactive T lymphocyte-mediated HSPC dysfunction and pancytopenia. Our findings provide new insights for the development of novel irisin-based regimens with enhanced protective effects against AA.
Single-Cell and Bulk RNA Sequencing Reveal MCL1 as a Key Regulator of Mitochondrial Function in Liver Ischemia-Reperfusion Injury.
Chen X, Xing S, Bao Y … +8 more , Yuan G, Gao W, Wang Y, Liu M, Zeng Y, Li Z, He S, Xiao F
FASEB J · 2026 Jul · PMID 42361133 · Publisher ↗
Liver ischemia-reperfusion injury (LIRI), a significant complication following liver transplantation and surgical procedures, remains inadequately addressed due to the limited therapeutic options available. This study ai...
Liver ischemia-reperfusion injury (LIRI), a significant complication following liver transplantation and surgical procedures, remains inadequately addressed due to the limited therapeutic options available. This study aims to elucidate the pivotal regulators underlying the maladaptive immune responses and mitochondrial dysfunction associated with LIRI. By integrating multiple microarray datasets (GSE12720, GSE112713, GSE23649, and GSE151648) and single-cell RNA sequencing (scRNA-seq) data (GSE171539), we employed weighted gene co-expression network analysis (WGCNA) alongside four machine learning algorithms (SVM, LASSO, RF, and XGBoost) to identify hub genes. Our analyzes highlighted MCL1 as a critical hub gene linked to mitochondrial function, exhibiting significantly elevated expression levels in LIRI, coupled with strong diagnostic accuracy. Further single-cell analysis revealed MCL1's specific enrichment in endothelial cells (ECs) and macrophages (MCs), along with the identification of a novel macrophage subset (CSF1RIL-1BMCL1) characterized by a dual pro-inflammatory and pro-survival phenotype. This finding suggests enhanced intercellular crosstalk involving key pathways such as NF-κB, apoptosis, and cytokine signaling, while in silico knockout of MCL1 markedly disrupted immune-related gene networks. Validation studies confirmed MCL1 upregulation and the presence of the macrophage subset in a murine LIRI model. In conclusion, our findings position MCL1 as a vital regulator linking immune inflammation and mitochondrial dysfunction in LIRI, proposing it as a promising diagnostic biomarker and therapeutic target for managing this condition, though its optimal therapeutic direction requires further investigation.
Metformin Partially Attenuates Simvastatin-Induced Myotoxic Responses in C2C12 Myotubes Through Metabolic Adaptation.
He C, Wesselink M, Huijts JY … +4 more , Zhong Z, Eggelbusch M, Jaspers RT, Wüst RCI
FASEB J · 2026 Jul · PMID 42361123 · Full text
Metformin is the first-line therapy for type 2 diabetes mellitus and is commonly co-administered with statins for cardiovascular risk reduction. However, statins can cause statin-associated muscle symptoms, while metform...
Metformin is the first-line therapy for type 2 diabetes mellitus and is commonly co-administered with statins for cardiovascular risk reduction. However, statins can cause statin-associated muscle symptoms, while metformin itself exerts complex effects on skeletal muscle. Because both drugs influence cellular energy metabolism and stress-response pathways in skeletal muscle, their combined effects on muscle cells warrant investigation. C2C12 myotubes were treated with metformin (50 or 1000 μM) in the absence or presence of simvastatin (10 μM) for 24 h. Myotube morphology, differentiation, and fusion indices, myoblast proliferation, and expression of atrophy-, stress-, and metabolism-related genes were assessed. Phosphorylation of key metabolic and anabolic signaling proteins (AMPK/ACC and Akt/mTOR-p70S6K) was analyzed. Mitochondrial respiration was measured using Seahorse respirometry, and mitochondrial network organization was quantified by live-cell imaging. Simvastatin significantly reduced myotube diameter (p < 0.0001), impaired myogenic progression in differentiated myotubes (differentiation index, p < 0.0001; fusion index, p = 0.0152), and inhibited myoblast proliferation (p = 0.003). Simvastatin increased the atrophy markers (Trim63, Fbxo32), stress marker (Perk), and concurrently suppressed myogenic (Myod) and anabolic (p-p70s6k/p70s6k) activity. Simvastatin also induced a broad suppression of mitochondrial and glycolytic metabolism, accompanied by reduced expression of the metabolic genes (Glut4, Hk2) and disruption of mitochondrial network connectivity. Co-exposure with metformin significantly attenuated simvastatin-induced effects, increasing myotube diameter (1.43-fold at low dose, p = 0.0223, and 1.48-fold at high dose, p = 0.0131), differentiation index (low dose: 1.63-fold; high dose: 1.80-fold; both p < 0.0001), and fusion index (low dose: 1.35; high dose: 1.50-fold; both p < 0.01). Compared with simvastatin alone, co-treatment with high-dose metformin increased AMPK and ACC phosphorylation and further suppressed mTOR signaling without amplifying atrophy-related gene expression. Despite deeper suppression of metabolic parameters (routine respiration, ATP production, Hk2 expression), metformin preserved mitochondrial network structure, increased Ppargc1a expression, and reduced cellular stress markers (Hri, Perk, Atf4). Simvastatin induced metabolic suppression, mitochondrial dysfunction, and atrophy-related responses in skeletal muscle cells. Metformin partially attenuated these alterations by preserving myotube structural integrity and reducing cellular stress signaling despite further metabolic suppression. These findings suggest that metformin may promote adaptive metabolic responses that enhance cellular resilience during simvastatin-induced metabolic stress.
Targeting the HMGB1 Pathway With Glycyrrhizic Acid and Amlexanox Attenuates RSV-Induced Injury and Viral Propagation.
Zhang P, Luo M, Lin S … +7 more , Hu S, Ling P, Wang G, Dai Y, Cui X, Luo YS, Zhang K
FASEB J · 2026 Jul · PMID 42359623 · Publisher ↗
Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections globally, with particularly severe implications for infants and the elderly population. Despite the substantial burden on public heal...
Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections globally, with particularly severe implications for infants and the elderly population. Despite the substantial burden on public health, effective therapeutic options for the treatment of RSV infections remain limited. The pathogenesis of RSV is characterized by complex inflammatory responses, while high-mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, is known to play a role in amplifying inflammation. However, the specific role of HMGB1 in RSV infection has not been thoroughly investigated. This study aims to elucidate the role of HMGB1 in RSV replication and to evaluate its potential as a target for antiviral therapy. The interaction between the RSV nucleocapsid (N) protein and HMGB1 was demonstrated through co-immunoprecipitation and mass spectrometry. Knockdown or overexpression of HMGB1 by small interfering RNA or pCMV-HA-HMGB1 resulted in a significant reduction or induction in RSV replication in vitro, thereby confirming the critical role of HMGB1 in viral propagation. Moreover, structure-based molecular docking analyses identified glycyrrhizic acid (GA) and amlexanox (AMX) as high-affinity ligands for HMGB1. In cellular studies, both GA and AMX effectively inhibited RSV replication in a dose-dependent manner while selectively suppressing HMGB1's secretion to the cytoplasm or extracellular space from RSV-infected cells. AMX was found to down-regulate HMGB1 expression while GA did not. In experiments using lethal murine RSV infection models, treatment with GA and AMX significantly improved survival rates and reduced lung pathology. In conclusion, these findings suggest that HMGB1 is a promising therapeutic target for RSV infection and highlight GA and AMX as potential antiviral candidates that can modulate HMGB1-mediated immunopathology.
Zinc Inhibits BTK Phosphorylation in Macrophages to Ameliorate Encephalitis in Neurotropic Virus-Infected Mice.
Sun X, Zhang B, Zhao S … +6 more , Liu H, Wang R, Yang D, Tian T, Qi L, Wei B
FASEB J · 2026 Jun · PMID 42340066 · Publisher ↗
Zinc is an essential micronutrient with well-characterized immunomodulatory properties and has been widely investigated in viral infectious diseases, yet its specific functional role in neurotropic viral encephalitis rem...
Zinc is an essential micronutrient with well-characterized immunomodulatory properties and has been widely investigated in viral infectious diseases, yet its specific functional role in neurotropic viral encephalitis remains poorly elucidated. In this study, we demonstrate that a zinc-supplemented (ZnS) dietary intervention confers protection against Japanese encephalitis virus (JEV) infection by suppressing macrophage-mediated inflammatory pathology in the central nervous system (CNS). Besides, zinc inhibited the phosphorylation of Bruton's tyrosine kinase (BTK) and NF-κB p65 in macrophages, thereby effectively curbing excessive neuroinflammation and alleviating JEV-induced neuronal damage in the murine brain. Our findings have identified a previously unrecognized mechanism by which zinc regulates immune responses in the central nervous system, and suggest zinc supplementation as a potential intervention for neurological complications arising from central nervous system infections.
Inflammatory Stewardship-A Perspective for Active Management of Acute Inflammation.
Herrlich LF, Schrezenmeier H, Messerer DAC
FASEB J · 2026 Jun · PMID 42340056 · Full text
Major surgery and traumatic injury are potent triggers of systemic inflammation. While appropriately regulated inflammation supports host defense and tissue repair, dysregulated and time-dependent inflammatory trajectori...
Major surgery and traumatic injury are potent triggers of systemic inflammation. While appropriately regulated inflammation supports host defense and tissue repair, dysregulated and time-dependent inflammatory trajectories contribute to postoperative and post-traumatic complications, organ dysfunction, prolonged disability, and mortality. Translation of mechanistic insight into effective bedside strategies has been limited by marked inter-individual heterogeneity, rapid phase shifts in the inflammatory response, and the absence of operational workflows that measure inflammation with sufficient biological and temporal resolution to guide patient-specific decisions. This perspective introduces 'inflammatory stewardship' as a precision-medicine paradigm for proactive management of acute inflammation in perioperative and critical care settings. Inflammatory stewardship integrates two core components: inflammatory staging and biomarker-guided immunomodulation. Inflammatory staging uses serial, multidimensional monitoring to characterize trajectories and to determine whether a patient's current inflammatory status lies within an individualized target range. Monitoring may combine routinely available clinical parameters with more specific immune phenotyping, functional assays, and molecular signatures, provided that assays are standardized, clinically interpretable, and available within actionable turnaround times. Biomarker-guided immunomodulation then links off-target trajectories to patient-specific escalation or de-escalation strategies, supported by predefined safety criteria and interdisciplinary governance. This perspective outlines key implementation requirements and a research agenda to establish reference trajectories, validate actionable endotypes, and embed biomarkers into adaptive interventional study designs. Inflammatory stewardship offers a testable roadmap to operationalize personalized inflammation management after surgery and trauma, aiming to enable earlier detection of maladaptive trajectories and more effective, patient-tailored immunomodulatory care in intensive care.
Integrating Machine Learning and Single-Cell Analysis to Reveal the Diagnostic and Therapeutic Value of Regulated Cell Death Mechanisms in Hepatocellular Carcinoma.
Chen J, Yang Z, Cui Y … +7 more , Zhao Z, Wu X, Cao J, Deng D, Yu M, Zhang X, Zhang X
FASEB J · 2026 Jun · PMID 42338358 · Publisher ↗
Hepatocellular carcinoma (HCC) treatment faces significant challenges, particularly in tumor growth, metastasis, and drug resistance. While several predictive models exist, effective models that accurately predict patien...
Hepatocellular carcinoma (HCC) treatment faces significant challenges, particularly in tumor growth, metastasis, and drug resistance. While several predictive models exist, effective models that accurately predict patient prognosis and guide targeted therapy decisions remain insufficient. Regulated cell death (RCD) pathways play a pivotal role in the development and progression of various cancers, offering potential prognostic indicators and biomarkers of drug sensitivity for HCC patients. We analyzed multi-cohort transcriptomic data (TCGA, GSE14520, ICGC) and single-cell RNA sequencing data (GSE149614) to identify differentially expressed RCD-related genes (DEGs). A prognostic model, the Regulated Cell Death Index (RCDI), was constructed using machine learning algorithms to stratify HCC patients into high- and low-RCDI groups. Single-cell analysis was employed to examine tumor microenvironment heterogeneity between these groups, and drug sensitivity analysis assessed differences in immune therapy, targeted therapy, and chemotherapy responses based on RCDI subgroups. RCDI was significantly associated with poor clinical features and shorter overall survival, with results validated across all cohorts. Enrichment analysis revealed that high RCDI is correlated with key cancer-related pathways, including the PI3K-Akt pathway and cell cycle regulation. High RCDI was also associated with immune cell infiltration and the expression of immune checkpoint molecules, as validated through single-cell RNA sequencing. Patients with high RCDI exhibited higher sensitivity to several targeted therapies, including Vorinostat and Trametinib. Further prioritization analyses identified EEF1E1, ITGB3BP, and SPP1 as promising candidate biomarkers with potential diagnostic and prognostic relevance. The RCDI model effectively stratifies HCC patients based on RCD-related molecular features, providing a valuable tool for predicting survival and therapeutic responses. The identification of key genes offers new insights into the molecular mechanisms of HCC and potential therapeutic targets.
Genetic Correlation and Causal Inference Between Female Fat Distribution and Preeclampsia: An Integrative Genomic Study.
Wang M, Huang L, Zhang D … +3 more , Yang F, Wu L, Gao B
FASEB J · 2026 Jun · PMID 42334105 · Full text
Preeclampsia (PE) is a major cause of maternal and perinatal morbidity. Because abnormal fat distribution is closely related to metabolic dysfunction, vascular injury, and hypertensive disorders during pregnancy, clarify...
Preeclampsia (PE) is a major cause of maternal and perinatal morbidity. Because abnormal fat distribution is closely related to metabolic dysfunction, vascular injury, and hypertensive disorders during pregnancy, clarifying its genetic relationship with PE may improve our understanding of adverse pregnancy outcomes. Here, we investigated the shared genetic architecture between PE and waist-hip ratio adjusted for body mass index (WHRadjBMI) by integrating large-scale genome-wide association study (GWAS) summary statistics for female WHRadjBMI from the GIANT consortium (n ≈ 700 000) and PE from FinnGen R11 (7955 cases and 124 764 controls). Analyses included genome-wide genetic correlation, polygenic overlap, local genetic correlation, cross-trait GWAS meta-analysis, tissue/cell type enrichment, functional annotation, and Mendelian randomization, using tools including linkage disequilibrium score regression (LDSC), MiXeR, LAVA, ρ-HESS, MTAG, CPASSOC, and conjunctional false discovery rate (conjFDR). We identified approximately 0.5 k shared causal variants; MiXeR detected a modest but significant polygenic overlap (rg = 0.08, p = 0.006), whereas LDSC showed no significant genome-wide correlation. A shared genetic locus near MTHFR-CLCN6 (rs17367504) was detected, consistent with known PE biology. Enrichment analyses implicated VEGFA-driven vascular and immune processes, with uterine pericytes displaying the strongest shared cell-type enrichment. Mendelian randomization supported a causal effect of WHRadjBMI on PE (IVW: p = 2.7 × 10) but not reverse causation. These findings suggest that genetically predicted fat distribution may contribute to PE susceptibility and highlight shared vascular-immune pathways that may link WHR-related genetic risk to pregnancy complications.
Protective Effects of Taurine Against Zearalenone-Induced Quality Impairment During Porcine Oocyte Maturation.
Wei YN, Meng QY, Weise A … +3 more , Hou YX, Ma RJ, Sun SC
FASEB J · 2026 Jun · PMID 42333697 · Publisher ↗
Zearalenone (ZEN) is a common non-steroidal estrogenic mycotoxin that exists widely in contaminated feeds, and its toxicities target multiple organs, especially the reproductive system, since ZEN is shown to affect oocyt...
Zearalenone (ZEN) is a common non-steroidal estrogenic mycotoxin that exists widely in contaminated feeds, and its toxicities target multiple organs, especially the reproductive system, since ZEN is shown to affect oocyte quality. In the present study, we reported that taurine (TAU), a sulfur-containing amino acid that exhibits antioxidant properties, protected the maturation quality of ZEN-exposed porcine oocytes. We showed that TAU significantly reversed the cumulus cell expansion and polar body extrusion defects of porcine oocytes under ZEN treatment. The rescue effect of TAU was attributed to its regulation of mitochondrial functions, which recovered mitochondrial membrane potential (MMP), mitochondrial quantity and mitochondrial fission. This further balanced reactive oxygen species (ROS) levels and reduced early apoptosis and DNA damage of porcine oocytes. The protection of TAU was confirmed by the integrity of subcellular cytoskeleton dynamics of oocytes, since microtubule stability-related spindle morphology and actin nucleation-related actin assembly were all preserved upon TAU supplementation. Furthermore, we showed that TAU reduced GRP78-dependent ER stress and autophagy levels and protected Rab10-mediated vesicular transport, which further ensured the organelle distribution, such as ER, lysosomes, and Golgi apparatus. In conclusion, our study demonstrated that TAU effectively alleviated ZEN-induced impairment of porcine oocyte developmental competence.
Cytochrome P450 1a (CYP1A)-Knockout Javanese Medaka Fish Exhibit Diabetic Traits and Reduced Reproductive Capacity.
Rusni S, Yoshioka Y, Pratiwi HM … +8 more , Takagi T, Royan MR, Hojo Y, Uno S, Kanda S, Takehana Y, Kinoshita M, Inoue K
FASEB J · 2026 Jun · PMID 42333022 · Full text
Cytochrome P450 1A (CYP1A) is an enzyme localized in the endoplasmic reticulum of liver cells. Although its roles in detoxification of exogenous substances have been investigated, its endogenous functions remain poorly u...
Cytochrome P450 1A (CYP1A) is an enzyme localized in the endoplasmic reticulum of liver cells. Although its roles in detoxification of exogenous substances have been investigated, its endogenous functions remain poorly understood. Here, we compared liver transcriptomes of CYP1A-knockout (KO) Javanese medaka (Oryzias javanicus) with those of wild-type (WT) fish to determine the physiological roles of CYP1A. We identified 508 differentially expressed genes (DEGs), including genes involved in glucose metabolism that were highly upregulated, such as insulin, glucagon, and somatostatin. KO fish exhibited elevated blood glucose levels, increased liver mass, and higher hepatic triglyceride levels, together with upregulation of glucose-regulatory genes, suggesting insulin resistance and a diabetic-like condition. In addition, some genes associated with reproduction, including zona pellucida sperm-binding proteins 1 and 3 (ZP1 and ZP3), were downregulated. Decreased spawning rates and fertilization rates confirmed reduced reproductive capacity in KO fish. Thus, this study demonstrates that CYP1A has endogenous functions in glucose homeostasis and reproduction. The CYP1A-KO strain is expected to serve as a model for investigating detailed physiological processes related to diabetes and reproductive mechanisms, as well as the relationship between these processes mediated by CYP1A.
Integrated Machine Learning and SHAP Analysis Identifies TRIM21 Ubiquitination of HSPA8 Driving Progression of Metabolic Dysfunction-Associated Fatty Liver Disease.
Zhang L, Xu R, Yu C … +2 more , Dai L, Zhang Z
FASEB J · 2026 Jun · PMID 42329327 · Publisher ↗
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a metabolic disorder characterized by excessive hepatic lipid accumulation. Despite its rapidly increasing global prevalence, the molecular mechanisms drivi...
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a metabolic disorder characterized by excessive hepatic lipid accumulation. Despite its rapidly increasing global prevalence, the molecular mechanisms driving MAFLD initiation and progression remain incompletely understood. Identification of key regulatory molecules may provide novel diagnostic and therapeutic targets. Key pathogenic genes associated with MAFLD were identified using machine-learning approaches integrated with SHapley Additive exPlanations (SHAP) analysis. Spearman correlation analysis was performed to assess the relationships between HSPA8 expression and immune cell infiltration, inflammatory cytokine levels, and lipid metabolism-related gene expression. An in vitro MAFLD model was established by treating HepG2 cells with oleic acid (OA) and palmitic acid (PA). Western blotting and co-immunoprecipitation assays were conducted to validate the interaction between TRIM21 and HSPA8. A noninvasive diagnostic model for MAFLD was constructed using a random forest (RF) algorithm based on seven endoplasmic reticulum-related genes (HSPA8, CDKN1A, CEBPB, BBC3, EGR1, FOS, and SCD). SHAP-based interpretability analysis demonstrated that these genes collectively contributed to model performance, with HSPA8 exerting the strongest influence. HSPA8 expression was significantly upregulated in MAFLD and showed strong correlations with NAFLD activity score, immune cell infiltration, inflammatory cytokine secretion, and lipid metabolism-related gene expression. Suppression of HSPA8 markedly attenuated lipid accumulation in OA- and PA-treated HepG2 cells. Mechanistically, TRIM21 was identified as an upstream E3 ubiquitin ligase that promoted K48-linked polyubiquitination of HSPA8, thereby facilitating its ubiquitin-proteasome-mediated degradation. HSPA8 was identified as a central pathogenic driver in MAFLD, while dysregulation of the E3 ubiquitin ligase TRIM21 exacerbated disease progression by destabilizing HSPA8. These findings highlight the TRIM21-HSPA8 axis as a potential diagnostic and therapeutic target in MAFLD.
RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.
Adella A, van Katwijk SB, Leermakers PA … +9 more , van Ham WB, de Ruiter H, Ilgutytė J, Hendrickx S, Nijland L, de Boer TP, van Rooij E, Hoenderop JGJ, de Baaij JHF
FASEB J · 2026 Jun · PMID 42329298 · Full text
Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) is a hereditary disorder characterized by kidney tubulopathy and dilated cardiomyopathy (DCM). RagD, encoded by the RRAGD gene, is a small GTPase...
Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) is a hereditary disorder characterized by kidney tubulopathy and dilated cardiomyopathy (DCM). RagD, encoded by the RRAGD gene, is a small GTPase involved in activating the mechanistic target of rapamycin complex 1 (mTORC1) by amino acids. Although several gain-of-function variants in the RRAGD gene have been identified, their contributions to DCM remain unclear. Here, we hypothesize that these RRAGD variants induce mTORC1 overactivation, thereby contributing to the manifestation of DCM. To investigate this, we established T-REx HeLa cell lines that overexpress the RRAGD p.(Ser76Leu) or the wild-type (WT) variant to assess the effects on mTORC1 signaling. Additionally, we developed the first cellular model of ADKH-RRAGD utilizing genetically edited human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express the mutated variant. Our data indicate that the RRAGD p.(Ser76Leu) variant maintains the phosphorylation of mTORC1 targets (i.e., S6K, 4E-BP1, and TFEB) during amino acid starvation, in contrast to RRAGD WT in T-REx HeLa cells. The pharmacological inhibition of mTOR with Torin1 reversed these changes. In 2D-cultured RRAGD hiPSC-CMs, mTORC1 remained responsive to amino acid starvation. Results from bulk RNA sequencing showed an upregulation of pathways associated with cytoskeletal organization and a downregulation of muscle development in RRAGD hiPSC-CMs. Moreover, a prolonged duration of Ca transients was observed in the mutant cardiomyocytes. Altogether, our data demonstrate that gain-of-function variants in RRAGD cause mTORC1 activation in T-REx HeLa cells. Consequently, cardiomyocytes develop impaired intracellular Ca clearance and activation of transcriptional programs, suggesting dedifferentiation.
Proanthocyanidin-Rich Cranberry Extract Lowers Glycemia in Established Obesity by Delaying Glucose Absorption.
Beji S, Mouchiroud M, Tribouillard L … +14 more , Efole B, Perazza L, Favereaux L, Poirier A, Idris W, Gélinas Y, Varin TV, Rovère C, Anhê FF, Picard F, Laplante M, Marette A, Michaud A, Caron A
FASEB J · 2026 Jun · PMID 42328893 · Full text
Dietary polyphenols, including proanthocyanidins, have emerged as potential modulators of metabolic health. Evidence supports benefits on glucose and hepatic metabolism in diet-induced obesity. However, reported effects...
Dietary polyphenols, including proanthocyanidins, have emerged as potential modulators of metabolic health. Evidence supports benefits on glucose and hepatic metabolism in diet-induced obesity. However, reported effects vary widely across polyphenol sources and experimental design, and the key physiological mediators of benefit in established obesity remain incompletely defined. Moreover, ambient temperature, a key determinant of metabolic phenotype that may influence therapeutic responses, is rarely considered. Here we aim to determine the metabolic effects and mechanisms of action of a proanthocyanidin-rich cranberry extract (PRCE) in established diet-induced obesity under cold (10°C) and thermoneutral (30°C) housing conditions. Male mice with established obesity were supplemented with PRCE or vehicle while housed at 10°C or 30°C. Metabolic phenotyping included body composition, glucose homeostasis, intestinal carbohydrate digestion and glucose absorption, circadian profiling of peripheral and central clocks, and gut microbiota analysis. PRCE supplementation significantly improved glycemia and glucose tolerance independently of temperature, without altering body weight, adiposity, thermogenic gene expression, or circadian expression of clock genes centrally and peripherally. Mechanistically, PRCE inhibited α-amylase activity and delayed early intestinal glucose absorption. These effects were accompanied by selective remodeling of the gut microbiota, including increased abundance of Akkermansia muciniphila. We conclude that PRCE improves glucose homeostasis in established obesity through intestinal mechanisms involving reduced carbohydrate digestion, delayed glucose absorption, and selective remodeling of the gut microbiota.
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