FASEB Journal[JOURNAL]
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200 papers
Passage-Dependent Size Distributions of Human-Derived Cells: Implications for Metabolic Assays.
Botte E, Mancini P, Magliaro C … +1 more , Ahluwalia A
FASEB J · 2026 Jun · PMID 42268592 · Full text
Biological noise is ubiquitous in living systems; yet, it is often neglected in cell-based experiments, potentially biasing data interpretation. We provide a quantitative characterization of single-cell equivalent diamet...
Biological noise is ubiquitous in living systems; yet, it is often neglected in cell-based experiments, potentially biasing data interpretation. We provide a quantitative characterization of single-cell equivalent diameter distributions in six human cell types using cell counting. By analyzing thousands of cells over passage number, we show that cell size is phenotype dependent and varies significantly with passage, with most cell types exhibiting a progressive reduction in median diameter. This variability is structured: When diameters are converted to masses, the distributions obey scaling laws, revealing conserved statistical properties of human cells in culture. Because key physiological processes such as metabolism scale with cell mass, passage-dependent shifts in diameter distributions can propagate into functional readouts. We show that changes in cell size are sufficient to bias estimates of construct-level metabolic rate, potentially confounding the interpretation of size-normalized assays and treatment effects. Our results highlight that biological noise in vitro is a source of statistical structure that enables scaling analyses and a dynamic property that, if ignored, can lead to systematic misinterpretation of experimental outcomes. Accounting for size distributions and their evolution over passages may therefore improve experimental design, data interpretation, and, ultimately, the translatability of in vitro models.
eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
Lin Y, Xia J, Li M … +7 more , Zhang J, Mu Y, Ling L, Lu M, Wang J, Liao K, Cai Y
FASEB J · 2026 Jun · PMID 42268574 · Publisher ↗
Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and...
Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.
Glucocorticoid Receptor Translational Isoforms Generate Unique Glucocorticoid Responses in the Mouse Brain.
Oakley RH, Sueyoshi T, Ramamoorthy S … +6 more , Nikolova VD, Goulding DR, Li J, Ray MK, Moy SS, Cidlowski JA
FASEB J · 2026 Jun · PMID 42268251 · Full text
Glucocorticoids are primary stress hormones necessary for life that act on nearly every tissue in the body to maintain homeostasis. These hormones and their synthetic derivatives are widely used in the clinic to combat d...
Glucocorticoids are primary stress hormones necessary for life that act on nearly every tissue in the body to maintain homeostasis. These hormones and their synthetic derivatives are widely used in the clinic to combat disease but are limited by serious adverse effects. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). In addition to the classic full-length receptor (GR-A), seven highly conserved receptor isoforms with progressively shorter N-terminal transactivation domains (NTD) (GR-B, GR-C1, GR-C2, GR-C3, GR-D1, GR-D2, GR-D3) are produced from the single GR gene by alternative translation initiation. To investigate the physiological function of these isoforms, we developed knockin mice that express GR-A but lack the GR NTD translational isoforms. Analyses of the hippocampal transcriptome from wild-type and GR-A knockin mice treated with dexamethasone (Dex) revealed three classes of Dex-regulated genes: genes dependent on GR-A alone, genes dependent on the GR NTD translational isoforms, and genes dependent on GR-A only under conditions of GR NTD isoform deficiency. The genes dependent on the GR NTD isoforms were preferentially associated with circadian rhythm signaling, synaptic function, and cognition. Consistent with these gene enrichment results, the GR-A knockin mice exhibited alterations in hypothalamic-pituitary-adrenal axis activity and fear-motivated contextual learning. The GR NTD translational isoforms formed distinct molecular complexes with GR-A and with each other, providing a mechanistic basis for their unique transcriptional signatures. These findings demonstrate that the GR NTD translational isoforms contribute to the actions of glucocorticoids in the brain by generating heterogeneity in glucocorticoid signaling.
Context-Dependent Effects of Apolipoprotein A2 on Lipid Metabolism and Atherogenesis.
Zvintzou E, Fenyo IM, Ionita R … +7 more , Kakafoni G, Dumitrescu M, Alemi M, Daraban BS, Marinos K, Gafencu AV, Kypreos KE
FASEB J · 2026 Jun · PMID 42268249 · Full text
Apolipoprotein A2 (APOA2) is a component of several plasma lipoproteins, yet its physiological and pathological functions remain unclear. Conflicting data regarding its effects on plasma lipid levels and cardiovascular r...
Apolipoprotein A2 (APOA2) is a component of several plasma lipoproteins, yet its physiological and pathological functions remain unclear. Conflicting data regarding its effects on plasma lipid levels and cardiovascular risk indicate that APOA2 activity may be context dependent. Here, we employed adenovirus-mediated gene transfer of human APOA2 into male C57BL/6, ldlr, and apoe mice fed a western-type diet for 2 weeks to investigate in parallel its impact on lipoprotein metabolism and atherogenesis under different conditions of dyslipidemia and atherosclerotic burden. In normolipidemic C57BL/6 mice, APOA2 expression raised plasma VLDL/LDL cholesterol and triglycerides, consistent with inhibition of lipoprotein lipase activity. In HDL density fractions, cholesterol was unaffected while triglycerides increased. In contrast, APOA2 expression in ldlr mice reduced cholesterol and triglyceride levels across all major lipoprotein fractions, including HDL density fractions. Similarly, in apoe mice, APOA2 expression markedly lowered VLDL cholesterol and triglycerides, though cholesterol and triglycerides in LDL and HDL density fractions were increased. Interestingly, following oral administration of olive oil containing [C]-cholesterol and [H]-triolein to ldlr mice, APOA2 expression enhanced tracer deposition in the aorta and aortic root. Corroborating this finding, immunohistochemical analysis of aortic root cryosections from both ldlr and apoe mice revealed increased staining for APOA2 and APOB in APOA2-expressing animals, suggesting augmented accumulation of APOB-containing lipoproteins in the arterial wall. Collectively, these findings support a pro-atherogenic role for APOA2. Although under dyslipidemic conditions APOA2 may superficially appear protective by lowering circulating APOB-containing lipoproteins, mechanistic evidence indicates that it promotes vascular retention of APOB-containing particles, thereby accelerating atherogenesis.
FABP4 Disrupts Redox Homeostasis Through GOT2 Interaction to Drive Macrophage Mitochondrial Lipid Metabolic Reprogramming in Atherosclerosis.
Zhang X, Yi Q, Liang H … +3 more , Li J, Zeng Y, Li C
FASEB J · 2026 Jun · PMID 42268241 · Publisher ↗
This study aims to investigate the role of fatty acid-binding protein 4 (FABP4) in macrophage lipid metabolism and inflammatory responses during atherosclerosis development, and to determine whether its function is media...
This study aims to investigate the role of fatty acid-binding protein 4 (FABP4) in macrophage lipid metabolism and inflammatory responses during atherosclerosis development, and to determine whether its function is mediated through interaction with glutamate oxaloacetate transaminase 2 (GOT2). Herein, macrophage-specific FABP4 knockout mice and RAW 264.7 macrophages were subjected to high-fat diet (HFD) or oxidized LDL (ox-LDL) treatment, respectively. Co-immunoprecipitation (Co-IP), qPCR, western blot, flow cytometry, ELISA, enzymatic assays, and histological staining (hematoxylin and eosin (H&E), Oil Red O) were used to assess protein interaction, expression, cytokine secretion, lipid accumulation, pro-inflammatory activation, and redox state. Macrophage-specific FABP4 deletion markedly reduced atherosclerotic plaque formation, lipid accumulation, pro-inflammatory cytokine levels, and the proportion of CD86 pro-inflammatory macrophages, while improving systemic lipid profiles. Mechanistically, FABP4 directly bound to mitochondrial GOT2 without altering its expression, leading to disruption of mitochondrial NADH/NAD redox homeostasis and subsequent metabolic dysfunction. Importantly, concurrent knockdown of GOT2 fully reversed the beneficial effects of FABP4 deficiency on lipid metabolism and inflammation, confirming GOT2 as a critical downstream mediator. FABP4 promotes atherosclerosis by binding to GOT2 and disrupting mitochondrial redox balance, thereby driving macrophage lipid metabolic reprogramming and inflammatory activation. Targeting the FABP4-GOT2 axis may offer a novel therapeutic strategy for atherosclerosis and related metabolic diseases.
Long Noncoding RNA SDRG Regulates Drosophila Neuromuscular Synapse Development by Modulating Frequenin 2 Through Coracle.
Cui M, Wang Y, Xu M … +5 more , Wei H, Bai B, Chen R, Liu L, Li M
FASEB J · 2026 Jun · PMID 42267849 · Publisher ↗
Synapses are specialized structures for information exchange between neurons and their targets, and precise regulation of synaptic growth is crucial for the formation and plasticity of neural circuits. The neuromuscular...
Synapses are specialized structures for information exchange between neurons and their targets, and precise regulation of synaptic growth is crucial for the formation and plasticity of neural circuits. The neuromuscular junction (NMJ) of fruit fly larvae is an excellent model for studying molecular mechanisms underlying synaptic development. There are few reports on the role of long noncoding RNAs (lncRNAs) in synaptic development at NMJ. Here, we reported a lncRNA, Synapse Development Regulatory Gene (SDRG), which regulates synaptic growth by antagonizing frequenin 2 (frq2) through Coracle (Cora). SDRG deficiency induced synaptic overgrowth characterized by excess satellite boutons at NMJ terminals, and simultaneously high frequenin 1 (frq1) and frq2 RNA levels. Genetically, frq2, not frq1, knock-down driven by motoneuron-specific Gal4 could rescue this growth defect, which was mediated by Cora protein. At the molecular level, SDRG promotes the recruitment of Cora protein to frq2 RNA. Our work exhibits a new function of lncRNA and is beneficial for unveiling the pathogenesis of neuropsychiatric disorders with abnormal synaptic development.
Mechanism and Intervention of the NPY1R/CREB Signaling Axis in Regulating Inflammatory Response in Aged Ovarian Granulosa Cells and Ovarian Senescence.
Fang J, Wang C, Guo S … +13 more , Zhang Y, Zhang Y, Wang H, Kong Y, Jin H, Qi L, Liu Y, Wu Z, Zhang F, Wen S, Wang X, Yang G, Yao G
FASEB J · 2026 Jun · PMID 42262763 · Full text
Ovarian senescence is accompanied by inflammatory responses, yet the underlying mechanism remains incompletely elucidated. In this study, transcriptome sequencing was performed on ovarian granulosa cells from advanced-ag...
Ovarian senescence is accompanied by inflammatory responses, yet the underlying mechanism remains incompletely elucidated. In this study, transcriptome sequencing was performed on ovarian granulosa cells from advanced-age patients and normal (Ctrl) patients, revealing that Neuropeptide Y Y1 Receptor (NPY1R) was significantly upregulated in aged granulosa cells. In vivo experiments confirmed that the NPY1R agonist [Leu, Pro]-NPY induced estrous cycle disorder, inhibited follicular development, triggered reactive oxygen species (ROS) accumulation and mitochondrial structural damage in oocytes, thereby inducing ferroptosis, and ultimately leading to ovarian dysfunction and compromised oocyte quality; conversely, the NPY1R antagonist BIBO 3304 effectively reversed these phenotypes. Mechanistic studies demonstrated that NPY1R overexpression activates the p-CREB signaling pathway, promotes the expression of pro-inflammatory factor IL-6 and inflammasome NLRP3, aggravates ferroptosis, mitochondrial dysfunction, and type I/III collagen imbalance, and ultimately accelerates ovarian aging. Collectively, this study clarifies that the NPY1R/CREB signaling axis participates in ovarian senescence by regulating inflammatory responses, and reveals its pivotal role in follicular development and oxidative stress. Targeting NPY1R is expected to be a potential therapeutic strategy for improving ovarian function and infertility in advanced-age women.
Retinoic Acid Informs the Positional Identity of Frontonasal Neural Crest Cells Through Alx Family of Transcription Factors.
Wu S, Lu Y, Tu Y … +5 more , Xi Y, Wan Q, Yue M, Liu H, Wu Z
FASEB J · 2026 Jun · PMID 42262729 · Full text
Cranial neural crest cells (CNCCs) give rise to the majority of the skeletal elements of the face. The precise morphogenesis of the face relies on highly coordinated actions of CNCCs, requiring each CNCC to obtain correc...
Cranial neural crest cells (CNCCs) give rise to the majority of the skeletal elements of the face. The precise morphogenesis of the face relies on highly coordinated actions of CNCCs, requiring each CNCC to obtain correct positional identity. As a diffusive signaling molecule, retinoic acid (RA) is known to regulate the positional identities along the anterior-posterior axis of the developing hindbrain by activating the Hox family of transcription factors. However, whether RA also has a direct role in regulating the positional identities of Hox-negative CNCCs, which give rise to the skeletal framework of the face, was unclear. In this study, we show that RA acts as a local environmental cue that patterns the Hox-negative CNCCs by activating the Alx family of transcription factors. We observed midfacial dysplasia and midline facial clefting in chick embryos after blocking RA signaling with an inverse pan-RAR agonist. Gene expression analysis revealed that this morphological defect is associated with the transformation of frontonasal neural crest identity toward a first pharyngeal arch (PA1)-like identity, a patterning defect that was also observed in Alx1 and Alx4 compound mutant mouse embryos. We further showed that both Alx1 and Alx4 are regulated by RA through cell-autonomous RA receptor (RAR) signaling. Mechanistically, RA signaling regulates Alx1 through an evolutionarily conserved distal enhancer located upstream of Alx1 within the intronic region of the gene Lrriq1, whereas the RA-responsiveness of Alx4 is conferred by its promoter. These findings establish a mechanistic linkage between RA signaling and Alx genes and provide novel insights into the craniofacial defects associated with disrupted RA signaling.
Correction to "Brain Proteomic Responses to Glucocorticoids and Their Relationship With Transcriptome: A Systematic Meta-Analysis".
FASEB J · 2026 Jun · PMID 42262671 · Publisher ↗
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H3.3K36me3 Reader ZMYND11 Localizes to Gene Promoter and Regulates Transcription Initiation.
Tian Y, Wang YF, Cai X … +3 more , Jiang XH, Zhou LQ, Yin Y
FASEB J · 2026 Jun · PMID 42262664 · Publisher ↗
ZMYND11 is the sole known reader of H3.3K36me3. It has been characterized as a transcriptional repressor that fine-tunes RNA polymerase II (Pol II) elongation through recognition of gene body-localized H3K36me3, based pr...
ZMYND11 is the sole known reader of H3.3K36me3. It has been characterized as a transcriptional repressor that fine-tunes RNA polymerase II (Pol II) elongation through recognition of gene body-localized H3K36me3, based primarily on earlier ChIP-seq data showing predominant ZMYND11 occupancy at gene bodies. However, subsequent data suggest that ZMYND11 may also localize to promoter regions. Here, using CUT&Tag assay, we demonstrate that ZMYND11 robustly occupies promoter regions in mouse ESCs and MEFs, with its promoter enrichment positively correlating with gene expression levels and Pol II occupancy. We further identify formaldehyde crosslinking as a critical factor causing signal loss at transcription start sites in conventional ChIP-seq. Mechanistically, ZMYND11 deficiency reduces the pausing index of Pol II, H3.3, and H3K36me3, indicating impaired transcription initiation. ZMYND11 knockout in mouse ESCs induces transcriptomic changes, impairs cell proliferation, and aberrantly activates 2-cell-specific transcriptional programs via ROS accumulation. Our findings reveal a previously unappreciated role for ZMYND11 as a transcriptional initiator that stabilizes Pol II at promoters, establishing its essential function in maintaining embryonic stem cell homeostasis and advancing our understanding of its context-dependent transcriptional regulatory mechanisms.
Correction to "The Evolutionally Conserved Activity of Dapper2 in Antagonizing TGF-β Signaling".
FASEB J · 2026 Jun · PMID 42262648 · Publisher ↗
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Integrated Multi-Omics Analysis and Experimental Validation Identify BCAT1 as a Critical Driver of Hepatocyte Pyroptosis in Acute-On-Chronic Liver Failure.
Li M, Lu B, Chen X … +8 more , Kang M, Wang G, Wang L, Ye H, Pu F, Wang M, Wen W, Chen Y
FASEB J · 2026 Jun · PMID 42258325 · Publisher ↗
Acute-on-chronic liver failure (ACLF) is characterized by profound metabolic dysfunction and high mortality. Identifying amino acid metabolism-related biomarkers is crucial for early diagnosis and therapeutic interventio...
Acute-on-chronic liver failure (ACLF) is characterized by profound metabolic dysfunction and high mortality. Identifying amino acid metabolism-related biomarkers is crucial for early diagnosis and therapeutic intervention. Amino acid metabolism-related genes (AAMGs) and ACLF transcriptomic data were integrated to identify core genes via weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Three machine learning (ML) algorithms-Random Forest, SVM-RFE, and Boruta-were applied to screen hub genes. Specific cellular profiles and immune landscapes were characterized using single-cell RNA sequencing (scRNA-seq) and ssGSEA. The pathological role of BCAT1 was investigated in APAP-induced ACLF models. A total of 26 genes were identified at the intersection of module genes, DEGs, and AAMGs. ML confirmed a three-gene signature (BCAT1, RPS6, OAT) with high diagnostic accuracy. ScRNA-seq analysis further verified that BCAT1 is predominantly expressed in hepatocytes, indicating its cell-type specific role in liver injury progression. In vitro and in vivo experiments demonstrated that BCAT1 exacerbates hepatocyte injury by activating the GSDMD/Caspase-1-mediated pyroptosis pathway. Our study reveals that BCAT1 is a pivotal driver of hepatocyte pyroptosis in ACLF. Targeting the BCAT1-mediated metabolic-inflammatory axis offers a promising therapeutic strategy for managing ACLF.
Low Zinc Ameliorated the Decrease in Intestinal Copper Level Induced by Low Dietary Copper: Involvement of SUMOylated-Mtf-1 and Mtf-1/Atp7a Pathway.
Zhong CC, Yang H, Hogstrand C … +4 more , Song CC, Zheng H, Huang C, Luo Z
FASEB J · 2026 Jun · PMID 42257536 · Publisher ↗
Copper (Cu) and zinc (Zn) are essential trace metal elements for vertebrates, and insufficient intake of trace metal elements can have adverse effects on animal health. Studies suggested that the interaction among trace...
Copper (Cu) and zinc (Zn) are essential trace metal elements for vertebrates, and insufficient intake of trace metal elements can have adverse effects on animal health. Studies suggested that the interaction among trace metal elements played a crucial role in this process. Therefore, the current study was conducted to explore whether low Zn alleviated low dietary Cu-induced decrease in intestinal Cu level and identify potential mechanisms via the in vivo animal experiment and in vitro cell culture. The regulatory relationship between metal response element binding transcription factor 1 (Mtf-1) and ATPase Cu transporting alpha (Atp7a) under low Cu and low Zn was elucidated through electrophoretic mobility shift assays and chromatin immunoprecipitation analysis. The SUMOylation modification of Mtf-1 and its effects on atp7a promoter were determined through immunoprecipitation and dual-luciferase reporter assay. Compared with the control, the low dietary Cu group significantly promoted the transcriptional regulation of atp7a promoter by Mtf-1, leading to intestinal Cu metabolism disorders. However, compared with the low dietary Cu group, the low Cu + low Zn group had significantly inhibited the transcriptional regulation of atp7a promoter by Mtf-1 and alleviated intestinal Cu metabolism disorder caused by low Cu. Mechanistically, Mtf-1 was modified by SUMOylation, and Sumo1-overexpression significantly reduced atp7a promoter activity. Taken together, dietary low Zn alleviated low Cu-induced decrease in intestinal Cu level through the SUMOylated-Mtf-1 and the Mtf-1/Atp7a axis.
FTO Regulates Porcine Adipogenesis and Postnatal Survival of Cloned Embryos.
Wang X, Zhang M, Yang Z … +8 more , Hu K, Zhu R, Yue Y, Zhu X, Xu W, Shi Z, Zhang Y, Cao Z
FASEB J · 2026 Jun · PMID 42257483 · Publisher ↗
The fat mass and obesity-associated gene (FTO), the first obesity-related gene and m6A demethylase, has well-defined roles in rodents but remains poorly understood in large mammals. Here, we combined siRNA-mediated knock...
The fat mass and obesity-associated gene (FTO), the first obesity-related gene and m6A demethylase, has well-defined roles in rodents but remains poorly understood in large mammals. Here, we combined siRNA-mediated knockdown, transcriptome sequencing, and bioinformatics to explore FTO function in porcine adipogenesis and embryo development. FTO silencing inhibited cell proliferation, promoted apoptosis, and suppressed adipogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) by downregulating key adipogenic genes (PPARγ, C/EBPα, FABP4, SCD, ACCα, LPL). Transcriptome analysis of CRISPR/Cas9-generated FTO-knockout fetal fibroblasts revealed altered pathways related to the cell cycle, senescence, apoptosis, and metabolism, including PI3K-Akt, Wnt, MAPK, and Apelin signaling. Using these knockout cells for somatic cell nuclear transfer (SCNT), we found that while FTO loss did not affect blastocyst formation, all cloned piglets carrying the mutation died postnatally. These results demonstrate that FTO is essential for porcine adipogenesis and postnatal survival of cloned embryos. The findings provided a new insight into the roles and mechanisms of FTO in fat metabolism and development in large mammals.
The Predictive Accuracy of Methods Commonly Used for Evaluating Animal Distress.
Leitner E, Thämlitz A, Khan MI … +4 more , Schulz B, Kumstel S, Vollmar B, Zechner D
FASEB J · 2026 Jun · PMID 42257378 · Full text
Accurate distress assessment is essential for ensuring animal welfare and scientific validity. Although behavioral and physiological indicators are commonly used, their predictive value across disease models and severity...
Accurate distress assessment is essential for ensuring animal welfare and scientific validity. Although behavioral and physiological indicators are commonly used, their predictive value across disease models and severity grades remains insufficiently defined. Here, we evaluated the discriminatory performance of body weight changes, distress scoring, burrowing, and nesting across ten datasets involving transmitter implantation, bile duct ligation (BDL), and chronic pancreatitis (CP) in mice. Receiver operating characteristic analyses determined the area under the curve (AUC), and optimal cut-offs derived from one dataset per model were applied to independent datasets to assess cross-project accuracy. Under moderate to high distress conditions, such as BDL and the acute phase after transmitter implantation, distress score showed excellent discriminative performance (AUC ≥ 0.96), while body weight, burrowing, and nesting also performed fair to excellent (AUC ≥ 0.76). In contrast, during low-distress conditions, including CP and recovery after implantation, discrimination was markedly reduced (body weight AUC ≥ 0.62; distress score, burrowing, and nesting AUC ≥ 0.50). When cut-offs were applied to independent datasets, distress score (≥ 96%) and body weight (≥ 86%) maintained high accuracy under moderate to high distress, whereas burrowing and nesting performed less reliably (≥ 65%). Accuracy declined further under low distress with body weight ≥ 56% and distress score ≥ 50%. Behavioral measures showed poor accuracy (burrowing ≥ 39%, nesting ≥ 19%). Overall, burrowing and nesting can support distress evaluation under moderate to high distress, but are less reliable than body weight and distress score, particularly under low-distress conditions.
Engineered Exosomes Deliver miR-370 Inhibitor to Regulate DNAJB1 and Synergize With miR-25 in Improving SCA3 Mice Behavior and Neuropathology.
Zhang Z, Gao S, Qin L … +1 more , He M
FASEB J · 2026 Jun · PMID 42253155 · Publisher ↗
Spinocerebellar ataxia type 3 (SCA3), the most common inherited ataxia, lacks effective therapies. Current microRNA (miRNA) approaches directly targeting ataxin-3 (ATXN3) mRNA risk reducing essential wild-type ATXN3, a k...
Spinocerebellar ataxia type 3 (SCA3), the most common inherited ataxia, lacks effective therapies. Current microRNA (miRNA) approaches directly targeting ataxin-3 (ATXN3) mRNA risk reducing essential wild-type ATXN3, a key regulator of proteostasis and various signaling pathways. Consequently, developing neuron-targeted, noninvasive miRNA delivery strategies that employ alternative mechanisms is critical for SCA3. In this study, we engineered rabies virus glycoprotein (RVG)-modified exosomes to deliver miR-370 inhibitors to the brains of SCA3 mice, thereby upregulating the molecular chaperone DnaJ homolog subfamily B member 1 (DNAJB1) to promote clearance of mutant ATXN3. Systemic administration of RVG-exosomes carrying miR-370 inhibitors led to increased DNAJB1 expression, reduced mutant ATXN3 aggregation, improved neuronal survival, and restored motor coordination in SCA3 mice. Furthermore, combining miR-370 inhibitors with miR-25-a miRNA that directly targets ATXN3 mRNA-synergistically enhanced the reduction of pathogenic ATXN3 and provided greater neuroprotection compared to either therapy alone. These findings support the use of RVG-exosome-mediated miR-370 inhibition as a noninvasive strategy to improve proteostasis in SCA3 and demonstrate its potential in combination with ATXN3 mRNA-targeting miRNAs, offering a promising therapeutic paradigm for SCA3 and similar neurodegenerative disorders.
WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts.
Yu G, Cui YL, Mu H … +4 more , Liu DM, Bao X, Zhou HY, Li HK
FASEB J · 2026 Jun · PMID 42253146 · Publisher ↗
Hepatocellular carcinoma (HCC) is the most prevalent subtype of primary liver cancer. Immunotherapy, particularly targeting immune checkpoints such as programmed cell death protein 1 (PD-1), has shown considerable therap...
Hepatocellular carcinoma (HCC) is the most prevalent subtype of primary liver cancer. Immunotherapy, particularly targeting immune checkpoints such as programmed cell death protein 1 (PD-1), has shown considerable therapeutic promise. Bioinformatic analysis of Gene Expression Omnibus datasets demonstrated significant upregulation of WNK lysine deficient protein kinase 4 (WNK4) expression in HCC tissues obtained from untreated patients or anti-PD-1 non-responders, suggesting a potential role for WNK4 in HCC progression and immunotherapy resistance. Through a series of experiments, we confirmed that WNK4 promoted the proliferative and migrative abilities of HCC cells and enhanced the resistance of HCC model mice to anti-PD-1 therapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), critically influences immunotherapy efficacy. The current study uncovered that WNK4 was transferred by HCC cell-derived exosomes into CAFs and promoted the cysteine metabolic reprogramming. Moreover, WNK4-mediated promotional effects of CAFs on the malignant phenotypes of HCC cells and anti-PD-1 resistance were in a cysteine-dependent manner. According to mechanism investigation, WNK4 could bind high mobility group box 1 (HMGB1) and induce its phosphorylation and cytoplasmic retention, thus reducing nuclear HMGB1-p53 interaction to enhance cystathionine gamma-lyase (CTH) expression. In summary, this study unveils a novel WNK4-HMGB1-p53 axis in CAFs that promotes HCC progression and modulates cysteine metabolism to foster immunotherapy resistance, offering potential therapeutic targets for HCC.
Timing of Coffee Intake Modifies Mortality Risk in Cardiovascular-Kidney-Metabolic Syndrome: A Cohort and Experimental Study.
Liu P, Yao G, Wu Y … +2 more , Ren H, Zhou Q
FASEB J · 2026 Jun · PMID 42253139 · Publisher ↗
The association between the timing of coffee consumption and mortality risk among individuals with cardiovascular-kidney-metabolic (CKM) syndrome remains unclear. This study aims to identify patterns of coffee intake tim...
The association between the timing of coffee consumption and mortality risk among individuals with cardiovascular-kidney-metabolic (CKM) syndrome remains unclear. This study aims to identify patterns of coffee intake timing and assess their links to all-cause and cause-specific mortality. This prospective cohort study included 21 553 adults with CKM syndrome from the 1999-2018 National Health and Nutrition Examination Survey. Two-step cluster analysis was used to identify temporal patterns of coffee consumption. Mortality risks were evaluated using weighted Cox proportional hazards regression models. Mouse models of CKM syndrome were established for different coffee consumption patterns. Over a median follow-up of 9.2 years, two coffee temporal patterns emerged: morning-type (47.7%) and late-day (5.3%). Among 3565 all-cause deaths, multivariable-adjusted models showed the morning-type pattern was associated with significantly reduced risks of all-cause (HR 0.79; 95% CI 0.65-0.97) and cardiovascular mortality (HR 0.75; 95% CI 0.50-0.97), independent of total intake and confounders. The relationship between coffee intake and all-cause mortality varied significantly by coffee temporal patterns (p-interaction = 0.035), with higher coffee consumption demonstrating inverse associations with all-cause mortality exclusively among morning-type consumers. In CKM mice, morning coffee improved metabolic and renal function, reduced cTnT and inflammatory markers (IL-6, IL-17A, CXCL1, CXCL2), while late-day coffee offered no benefits. Morning coffee consumption was more strongly associated with a lower risk of death in CKM than drinking coffee later. Our findings highlight the importance of coffee drinking timing in the association between coffee intake and health outcomes.
Sulconazole Suppresses Colorectal Cancer Immune Evasion by Inhibiting Glycolysis to Upregulate OVOL2 PARylation and Induce PANoptosis.
Zhang J, Li R, Zhuo Z … +7 more , Li L, Li Q, Mu S, He S, Chen W, Li L, Zhan W
FASEB J · 2026 Jun · PMID 42252920 · Full text
Colorectal cancer (CRC) progression involves metabolic reprogramming and immune evasion, but the link between glycolysis-driven epigenetics and immune checkpoints is unclear. OVOL2 is a tumor suppressor, yet its role in...
Colorectal cancer (CRC) progression involves metabolic reprogramming and immune evasion, but the link between glycolysis-driven epigenetics and immune checkpoints is unclear. OVOL2 is a tumor suppressor, yet its role in metabolic-immune crosstalk is unknown. In CRC cells and mouse models, we studied how OVOL2 loss enhances glycolysis and immune evasion. Multi-omics, CRISPR-Cas9, and pharmacological inhibition dissected the OVOL2-glycolysis-PD-L1 axis. Histone lactylation was assessed via immunoblotting and mutagenesis; OVOL2 PARylation by co-IP and PARP assays. Sulconazole's effects were tested in vitro/in vivo, with immune profiling by flow cytometry and multiplex IHC. OVOL2 deficiency increased glycolysis, lactate, and histone lactylation at the CD274 promoter, upregulating PD-L1 and promoting CD8+ T-cell exhaustion. Sulconazole inhibited glycolysis, reduced lactylation and PD-L1, and restored PARP1-mediated OVOL2 PARylation, inducing ASC-dependent PANoptosis. In mice, sulconazole suppressed tumor growth and metastasis. OVOL2 regulates metabolic-immune crosstalk in CRC. Sulconazole blocks glycolysis-driven PD-L1 expression and restores OVOL2 function, inducing PANoptosis and reversing immune evasion. Repurposing sulconazole offers a promising strategy for glycolytic, immunosuppressive CRC.
Dietary Fiber Polysaccharide Components Supplementation Modulate Uterine Immune Microenvironment to Support Embryo Implantation via SCFAs-Driven Tregs Differentiation.
Yang Y, Ma L, Hua L … +12 more , Jiang Y, Jiang X, Zhang R, Song C, Li H, Jin C, Che L, Feng B, Lin Y, Xu S, Zhuo Y, Wu D
FASEB J · 2026 Jun · PMID 42249776 · Publisher ↗
Regulatory T cells (Tregs) are essential for establishing maternal immune tolerance during embryo implantation. Dietary fiber, composed of diverse polysaccharides, has been shown to enhance Tregs populations and improve...
Regulatory T cells (Tregs) are essential for establishing maternal immune tolerance during embryo implantation. Dietary fiber, composed of diverse polysaccharides, has been shown to enhance Tregs populations and improve implantation outcomes, yet the specific components responsible remain unclear. In this study, we investigated the effects of polysaccharide components of dietary fiber, inducing polygalacturonic acid (PGA), arabinoxylan, and cellulose on embryo implantation. We found that PGA significantly promoted implantation, associated with an increased number of decidual Tregs. PGA also enhanced gut microbial diversity and elevated short-chain fatty acids (SCFAs) levels, particularly butyrate, which in turn promoted Tregs differentiation. In vitro, we demonstrated that butyrate enhances Tregs differentiation via GPR43-dependent signaling, which upregulates Tregs associated genes and may activate the adaptive immune response through JAK-STAT and PI3K-Akt pathways. These findings provide new insights into the role of dietary fiber in supporting early pregnancy and suggest novel strategies for preventing embryo loss.
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