FASEB Journal[JOURNAL]
Sun
200 papers
A ZBTB26-Integrator Axis Mediates Targeted Transcriptional Activation.
Yu D, Chen G, Lin F … +4 more , Cheng X, Qiao Z, Zhu P, Hu S
FASEB J · 2026 Jun · PMID 42219880 · Publisher ↗
The Integrator complex is primarily known to attenuate transcription by inducing premature termination of paused RNA polymerase II (RNAPII) and restraining pause release through its endonuclease and phosphatase activitie...
The Integrator complex is primarily known to attenuate transcription by inducing premature termination of paused RNA polymerase II (RNAPII) and restraining pause release through its endonuclease and phosphatase activities. However, the mechanisms that govern Integrator recruitment to chromatin and direct gene-specific transcriptional programs in response to external stimuli and diverse biological contexts remain poorly understood. In particular, the regulatory functions of the Integrator auxiliary or arm module (INTS10/13/14/15) are the least characterized. Here, we identify ZBTB26 as an interactor of the Integrator auxiliary module via INTS10 and INTS13, demonstrate its ability to directly bind a specific DNA motif, and show that it co-occupies select promoters and enhancers with Integrator and active histone markers across the genome. We demonstrate that ZBTB26 is required for the recruitment of Integrator to its target loci, including genes involved in stimulus response, development, and differentiation. Importantly, the ZBTB26-Integrator axis sustains the active state of specific promoters and enhancers and drives defined gene transcriptional programs. Our findings reveal a transcription factor-like mechanism of targeted gene regulation mediated by ZBTB26-Integrator binding, extending the functional paradigm of Integrator beyond its canonical catalytic roles.
LncRNA CASC15-EZH2 Interaction Promotes Ischemia-Reperfusion Induced Acute Kidney Injury via Regulating SALL1 and Wnt/β-Catenin Pathway.
Zhang M, Yan X, Mei S … +9 more , Ye Z, Li B, Yang S, Zhang M, Chi M, Wu M, Li H, Cheng F, Zhou X
FASEB J · 2026 Jun · PMID 42217179 · Publisher ↗
Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a critical role in various kidney diseases. Previous studies have demonstrated that EZ...
Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a critical role in various kidney diseases. Previous studies have demonstrated that EZH2 contributes to ischemia-reperfusion (I/R)-induced acute kidney injury (AKI). However, the specific role and regulation of EZH2 in renal I/R injury remain incompletely understood. This study provides a comprehensive analysis of EZH2's role and underlying mechanisms in renal ischemia-reperfusion injury. Inhibition of EZH2 reduces apoptosis and ameliorates I/R-induced AKI in both in vitro and in vivo models. Global gene expression analysis by RNA-seq and ChIP-seq reveals a marked upregulation of Spalt-Like Transcription Factor 1 (SALL1) and its involvement in the Wnt signaling pathway in EZH2-knockdown HK-2 cells. Mechanistically, Cancer Susceptibility Candidate 15 (CASC15) recruits EZH2 to the SALL1 promoter, where EZH2 catalyzes H3K27me3 modification. ChIP analysis further confirms the enrichment of EZH2 at the SALL1 promoter. Additionally, silencing of SALL1 exacerbates hypoxia-induced apoptosis in HK-2 cells through inactivation of β-catenin. In conclusion, CASC15 recruits EZH2 to the SALL1 promoter, where EZH2 mediates H3K27me3 modification to suppress SALL1, thereby regulating the Wnt/β-catenin signaling pathway in renal I/R injury. The CASC15/EZH2/SALL1 axis represents a promising therapeutic target for the treatment of AKI.
Localization of p210 BCR-ABL to the Mitochondria Promotes Chronic Myeloid Leukemia Cell Proliferation Through cIAP Signaling.
Ikegami A, Watanabe-Takahashi M, Shimasaki K … +10 more , Okuda Y, Choda M, Waku T, Maru Y, Deguchi A, Nishino Y, Miyazawa A, Shibata N, Naito M, Nishikawa K
FASEB J · 2026 Jun · PMID 42217178 · Publisher ↗
The chimeric protein p210 BCR-ABL is a major causative factor of chronic myeloid leukemia (CML). Previously, we found that p210 BCR-ABL translocates from the cytosol to the mitochondria upon mitochondrial damage via the...
The chimeric protein p210 BCR-ABL is a major causative factor of chronic myeloid leukemia (CML). Previously, we found that p210 BCR-ABL translocates from the cytosol to the mitochondria upon mitochondrial damage via the interaction of its pleckstrin homology domain (p210-PH) with cardiolipin (CL), a mitochondria-specific phospholipid. However, the precise pathological functions of this event are unknown. Here, using multivalent peptide library screens, we identified a tetravalent peptide, WDD-R4-tet, which binds to the CL-binding region of p210-PH and inhibits the translocation of p210 BCR-ABL to the mitochondria. Notably, WDD-R4-tet induced the apoptosis of CML cells by specifically suppressing the expression of cellular inhibitor of apoptosis 1 and 2 (cIAP1/2), ubiquitin ligases with anti-apoptotic functions, leading to the activation of caspases. Other compounds that inhibited cIAP1/2 also efficiently inhibited the proliferation of CML cells. Thus, WDD-R4-tet might be a novel therapeutic agent for CML, which functions by inhibiting novel cell-survival signaling pathways generated on the mitochondrial outer membrane of CML cells.
Targeting of Staphyloxanthin and α-Hemolysin by Natural Compound L-Malic Acid Suppresses Staphylococcus aureus Virulence.
Shen L, Wang B, Yang J … +9 more , Yuan X, Chen Z, Yang C, Fu J, Gao H, Han W, Shi J, Yu F, Yu J
FASEB J · 2026 Jun · PMID 42216777 · Publisher ↗
The escalating prevalence of antibiotic resistance in Staphylococcus aureus has underscored the urgent necessity for groundbreaking anti-infective therapies that target novel pathways. Metabolic intermediates, such as th...
The escalating prevalence of antibiotic resistance in Staphylococcus aureus has underscored the urgent necessity for groundbreaking anti-infective therapies that target novel pathways. Metabolic intermediates, such as those in the TCA cycle, have been known to be linked to bacterial virulence. L-Malic acid (L-MA), a natural TCA cycle intermediate, is known for its antimicrobial and antioxidant properties; however, its effect on the virulence of Staphylococcus aureus has yet to be explored. It was found that L-malic acid not only inhibited bacterial growth but also markedly reduced the production of crucial virulence factors, including staphyloxanthin and α-hemolysin. The suppression of pigment synthesis was primarily due to the competitive antagonism of CrtO, a key oxidoreductase responsible for carotenoid biosynthesis in Staphylococcus aureus, coupled with enhanced flux through the TCA cycle that redirected acetyl-CoA pools away from the mevalonate pathway. Moreover, hemolytic activity was decreased by lowering the expression of α-hemolysin. In vivo studies using mouse infection models further demonstrated that L-malic acid effectively mitigated the pathogenicity of Staphylococcus aureus, significantly reducing the formation of skin and liver abscesses. These findings position L-malic acid as a promising agent targeting Staphylococcus aureus infections, highlighting the need for further research into its therapeutic potential.
Activation of Sirt1 by Glyasperin F Suppresses PI3K/Akt/HIF-1α Signaling and Inhibits Glycolytic Metabolism to Ameliorate Pathology in Rheumatoid Arthritis-Associated Interstitial Lung Disease.
Yuan H, Leng W, Yu N … +5 more , Yu Y, Yang C, Bai Y, Xia X, Wang Y
FASEB J · 2026 Jun · PMID 42216775 · Publisher ↗
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe extra-articular complication with limited treatment options. This study identified Glyasperin F, a flavonoid derived from licorice and dried...
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe extra-articular complication with limited treatment options. This study identified Glyasperin F, a flavonoid derived from licorice and dried ginger decoction, as a potent inhibitor of glycolytic reprogramming in RA-ILD. Using a murine model combining collagen-induced arthritis and bleomycin-induced pulmonary fibrosis, we demonstrated that Glyasperin F significantly alleviated joint inflammation and pulmonary fibrosis. An in vitro inflammatory-fibrotic model was established by co-stimulating MRC-5 human lung fibroblasts with TGF-β1 and IL-1β. This model was combined with pharmacological modulation of Sirt1 using EX527 and SRT1720, as well as HIF-1α overexpression or empty-vector lentiviral transduction, to dissect the underlying molecular mechanisms. Mechanistically, Glyasperin F upregulated Sirt1, thereby suppressing the PI3K/Akt/HIF-1α pathway, downregulating key glycolytic enzymes (HK2, PFK, PKM2, LDHA), and reducing lactate/ATP production and oxidative stress. HIF-1α overexpression reversed these therapeutic effects. This study suggests that Glyasperin F has the potential to serve as a natural candidate compound for the regulation of glycolytic metabolism in the intervention of RA-ILD.
Immune-Adaptive Transcriptomic Networks Supporting Sustained Milk Production and Reproductive Longevity in Dairy Cows.
An Z, Jiang Y, Li W … +8 more , Chen K, Ding Q, Huang J, Li J, Wang H, Xia S, Li H, Shen Y
FASEB J · 2026 Jun · PMID 42216757 · Publisher ↗
In modern dairy systems, sustained milk production over the lifetime of a cow depends critically on maintaining reproductive efficiency across repeated lactation cycles. However, repeated lactation and advancing parity i...
In modern dairy systems, sustained milk production over the lifetime of a cow depends critically on maintaining reproductive efficiency across repeated lactation cycles. However, repeated lactation and advancing parity impose cumulative metabolic and inflammatory stress that often compromises fertility and shortens productive lifespan. Increasing evidence suggests that immune dysregulation contributes to parity-associated reproductive decline, raising the possibility that sustained milk production requires adaptive immune regulation. We hypothesized that cows achieving reproductive longevity exhibit parity-dependent immune remodeling that supports continued reproductive function and extended milk production. To test this hypothesis, we profiled blood transcriptomes from 131 Holstein cows spanning parities 1-9. Analysis of 17 422 expressed genes identified six distinct parity-associated expression trajectories, revealing coordinated transcriptomic remodeling with increasing reproductive history. Differential expression analysis identified 1 405 parity-associated genes enriched in immune- and stress-related pathways, including MAPK and Rap1 signaling. Weighted gene co-expression network analysis further identified immune-regulatory modules strongly correlated with parity and key reproductive indicators, suggesting a central role of immune adaptation in sustaining reproductive efficiency. Machine learning analysis of 256 genes in significantly enriched pathways with P-adjusted < 0.05 prioritized PDE4C, APLN, and CDH15 as potential key predictors of reproductive persistence. Integration with co-expression networks demonstrated that these genes may function as highly connected hub nodes within immune- and stress-responsive modules. Collectively, these results indicate that coordinated immune signaling networks are associated with reproductive persistence and thereby contribute to extended milk production in dairy cows. This study provides molecular insight into the immune mechanisms underlying productive longevity and identifies candidate biomarkers with potential applications in genomic selection and precision herd management.
FTO Regulates Autophagy and Energy Metabolism in Sepsis-Induced Cardiomyopathy: Insights From Integrated Transcriptome and Proteome Analysis.
Zhang Y, Xin Y, Wei E … +6 more , Ma W, Shen Y, Cheng S, Zhai A, Wang H, Wang W
FASEB J · 2026 Jun · PMID 42216755 · Publisher ↗
Sepsis-induced cardiomyopathy (SCM) is a severe complication of sepsis, characterized by profound cardiac dysfunction and high mortality, but its molecular mechanisms remain poorly defined. RNA epigenetic regulation, par...
Sepsis-induced cardiomyopathy (SCM) is a severe complication of sepsis, characterized by profound cardiac dysfunction and high mortality, but its molecular mechanisms remain poorly defined. RNA epigenetic regulation, particularly by the mA demethylase FTO, has been implicated in cardiovascular disease, yet its role in SCM is unclear. This study aimed to elucidate the function of FTO in SCM by integrating transcriptomic and proteomic analyses. A cecal ligation and puncture (CLP) mouse model was used for in vivo experiments, while lipopolysaccharide (LPS)-stimulated H9c2 cardiomyocytes were employed for in vitro studies to assess the expression and function of FTO. Transcriptomic and proteomic profiling of FTO-overexpressing cardiomyocytes was performed, followed by multi-omics integration analysis to identify key regulatory pathways and genes. The role of FTO in SCM was further validated using molecular and functional assays. CLP-induced septic mice exhibited progressive cardiac dysfunction. mA modification was increased while the expression of FTO was markedly reduced in vivo and in vitro. Multi-omics analysis of FTO-overexpressing cells revealed enrichment of autophagy and energy metabolism pathways. The integrated transcriptomic and proteomic profiling, coupled with MeRIP-qPCR validation, identified key FTO-regulated genes. Functionally, FTO overexpression restored autophagic flux and ATP production, whereas FTO knockdown exacerbated autophagic blockade and energy failure, establishing FTO as a central regulator of SCM pathogenesis. FTO acts as a critical regulator of autophagy and energy metabolism, conferring cardioprotection in SCM. This epitranscriptomic pathway adds a new layer of potential therapeutic targets for precision treatment in SCM.
Microbial Metabolite-Stimulated Bitter Taste Receptor T2R14 Signaling Is Modulated by CFTR Interactions.
Gupte T, Singh N, Bhatia V … +6 more , Arora K, Amiri S, Fernyhough P, Naren AP, Dakshinamurti S, Chelikani P
FASEB J · 2026 Jun · PMID 42216476 · Publisher ↗
Bitter taste receptors (TAS2Rs or T2Rs) are a subset of G protein-coupled receptors (GPCRs) that play a key role in responding to microbial presence at epithelial surfaces. We previously reported that mutations in the cy...
Bitter taste receptors (TAS2Rs or T2Rs) are a subset of G protein-coupled receptors (GPCRs) that play a key role in responding to microbial presence at epithelial surfaces. We previously reported that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect innate immune signaling from the bitter taste receptor T2R14, but the mechanisms remain understudied. Here we employ multiple biophysical tools to investigate T2R14 and CFTR interactions and its effect on signaling. The data indicate that either the N-terminus or the NBD2/C-terminus of CFTR can independently interact with agonist-stimulated T2R14. The T2R14 agonist required for interaction with CFTR may be either a chemically synthesized bitter compound or a microbial metabolite. Agonist-bound T2R14 can engage both Gαi and Gαq subunits. Interplay between T2R14, its agonists, and the specific interacting CFTR domain governs the bias of signaling between Gi and Gq pathways. Taken together, the analysis of protein-protein interactions and signaling outcomes provides a possible explanation for the altered T2R signaling in CFTR mutant cells.
Antibiotic-Loaded Polymethyl Methacrylate Cement Drives Fibroblast-Mediated Angiogenesis via LOXL2 to Accelerate Diabetic Foot Ulcer Healing.
Zhang Y, Luo D, Li R … +6 more , Lv F, Qahar M, Yang C, Qi F, Gao S, Wei Z
FASEB J · 2026 Jun · PMID 42213591 · Publisher ↗
Antibiotic-loaded polymethylmethacrylate (PMMA) cement (APC) improves healing in diabetic foot ulcers (DFUs), yet the cellular mechanisms underlying its pro-angiogenic effects remain unclear. This study aimed to identify...
Antibiotic-loaded polymethylmethacrylate (PMMA) cement (APC) improves healing in diabetic foot ulcers (DFUs), yet the cellular mechanisms underlying its pro-angiogenic effects remain unclear. This study aimed to identify key cell populations and molecular pathways by integrating scRNA-seq and proteomic profiling. DFU wound tissues, treated with APC or controls, were analyzed for differentially expressed proteins (DEPs) using label-free quantitative proteomics. Paired scRNA-seq identified APC-responsive cell populations, and pseudotime and BEAM analyses, integrated with proteomic data, pinpointed key regulatory genes. The analysis revealed that APC treatment specifically upregulated 63 DEPs. scRNA-seq of 20 245 cells identified six major cell types, with fibroblasts showing significant expansion and transcriptional changes. Further analysis identified LOXL2 as a central regulator of fibroblast remodeling. LOXL2 fibroblasts were enriched in healed wounds and promoted angiogenesis through ANGPTL2-ITGA5-mediated endothelial interactions. In vivo, LOXL2 facilitated wound closure and collagen deposition. Our findings suggest that LOXL2 emerges as a core molecular target for APC therapy in diabetic foot ulcers by reshaping fibroblast heterogeneity and enhancing fibroblast-endothelial cell communication.
Insights Into Dose-Dependent Bone Toxicity Following Partial-Body Exposure to Fractionated Ionizing Radiation In Vivo.
Wei F, Jennifer SS, Omer M … +9 more , Ngo C, Pugazhendhi AS, Yousefi N, Aceto M, Ghattas Y, Adhikary A, Walck CD, Seal S, Coathup MJ
FASEB J · 2026 Jun · PMID 42213589 · Publisher ↗
Bone toxicity resulting from ionizing radiation (IR) is a major contributor to bone loss, fracture, pain, and morbidity. However, the precise mechanisms that drive its development remain largely unknown, and no effective...
Bone toxicity resulting from ionizing radiation (IR) is a major contributor to bone loss, fracture, pain, and morbidity. However, the precise mechanisms that drive its development remain largely unknown, and no effective medical countermeasure exists. Deciphering the molecular mechanism and mode of action as well as discerning molecular biomarker signatures that manifest proportionate to the dose and severity of injury is crucial in expediting the discovery and development of novel and effective diagnostic, prognostic, and treatment approaches. Herein, we investigate and compare the response to high dose IR during the transition of bone-derived mesenchymal stem cells to osteoblasts and adipocytes, macrophages to osteoclasts, and late osteoblasts to mature osteocytes in vitro. Further, the counter response of bone to cumulative doses of 8, 16, and 24 Gy was assessed in vivo. Our findings indicate several novelties: cumulative radioresistance to DNA damage, apoptosis, reactive oxygen species formation, and dysfunctional mineral deposition was measured during osteoblast to osteocyte transition. Irradiation stimulated the formation of tunneling nanotube-like structures, a novel type of intercellular communication machinery, in exposed macrophages. Bone fracture stress but not ultimate stress significantly decreased 48 h after a single 8 Gy exposure and prior to microarchitectural deterioration in vivo. Thus, early frailty-inducing micromechanisms may originate within the organic/material component of bone independently of mechanical structure. Finally, data reveal dose- and severity-related proteomic signatures of pathological toxicity. Engineered approaches that therapeutically target these fundamental cellular processes may offer a promising future strategy for the prevention and treatment of IR-induced bone injury.
Aerobic Exercise Preserves Retinal Integrity in Type 2 Diabetic Zebrafish in Association With Skeletal Muscle Mitochondrial Homeostasis.
Gou S, Dai Z, Luo C … +12 more , Yu H, Wang L, Wang X, Chu X, Xi K, Chen R, He D, Duan C, Xu S, Zheng Z, Sun D, Zeng M
FASEB J · 2026 Jun · PMID 42205088 · Publisher ↗
Diabetic retinopathy is a major complication of type 2 diabetes mellitus (T2DM), yet effective early interventions that simultaneously address systemic metabolic dysfunction and retinal injury remain limited. Here, using...
Diabetic retinopathy is a major complication of type 2 diabetes mellitus (T2DM), yet effective early interventions that simultaneously address systemic metabolic dysfunction and retinal injury remain limited. Here, using a zebrafish model of T2DM under continued diabetic challenge, we show that aerobic exercise preserves retinal integrity in parallel with broad metabolic and mitochondrial adaptations. Aerobic exercise improved glucolipid metabolic status, attenuated skeletal muscle injury, restored mitochondrial ultrastructure, and increased ATP content and mitochondrial complex I and III activities. These changes were accompanied by reduced inflammatory and oxidative stress burden, reflected by lower IL-1β, IL-6, TNF-α, and MDA levels and higher CAT and SOD activities. Retinal injury was concurrently alleviated, as indicated by increased inner and outer nuclear layer thicknesses and reduced apoptosis, together with improvement in behavioral abnormalities. Correlation analyses further linked inflammatory and oxidative stress indices with mitochondrial energy metabolism-related indices and retinal structural measures. Collectively, these findings suggest that exercise-associated retinal protection occurs in parallel with improved systemic metabolic status and preservation of skeletal muscle mitochondrial homeostasis under diabetic conditions, highlighting aerobic exercise as a potential early strategy for limiting diabetes-associated retinal vulnerability.
miRNA Sensor HuR Compartmentalizes Ago2-Uncoupled miRNAs to Lipid Droplets to Buffer miRNA Activity in Mammalian Cells.
Chakraborty S, Bandyopadhyay D, Mukherjee K … +1 more , Bhattacharyya SN
FASEB J · 2026 Jun · PMID 42205075 · Publisher ↗
miRNA activity must be optimized to ensure target gene expression in mammalian cells in response to specific needs. How and when miRNA activity is regulated remains an open question in gene expression, with limited infor...
miRNA activity must be optimized to ensure target gene expression in mammalian cells in response to specific needs. How and when miRNA activity is regulated remains an open question in gene expression, with limited information on how the cellular machinery senses miRNA levels to regulate miRNA expression and activity. Because miRNAs are stable molecules that can be reversibly used, the existence of a miRNA-sensing mechanism in mammalian cells has been anticipated. With ectopic expression of miRNAs in mammalian cells, we found a dose-dependent miRNA buffering mechanism in which miRNA export and its storage on lipid droplets are essential for miRNA activity optimization in mammalian cells. We found that the miRNA-binding protein HuR, known for its role in miRNA export, has a dual function in mammalian cells. HuR uncouples miRNAs from Ago2 to facilitate association of lipid droplets with Ago-uncoupled miRNAs, a process that gets augmented in cells with high lipid droplet content and restricted extracellular export. Thus, HuR acts as a miRNA sensor, and the optimal activity and abundance of HuR regulate miRNA storage on lipid droplets or its export, thereby maintaining cellular miRNA homeostasis and preventing the detrimental effects of excessive miRNA content in mammalian cells. Thus, targeting miRNA export or lipid droplet association is an important strategy for buffering cellular miRNA levels.
Epigenetic Information Loss and Chronosenescence in Liver Aging: From Molecular Mechanisms to Therapeutic Interventions.
Xu X, Li H, Li J … +1 more , Huang M
FASEB J · 2026 Jun · PMID 42205070 · Publisher ↗
Liver aging involves progressive functional decline and increased susceptibility to metabolic diseases. Emerging evidence supports the view that some aspects of liver aging reflect partially reversible disruption of epig...
Liver aging involves progressive functional decline and increased susceptibility to metabolic diseases. Emerging evidence supports the view that some aspects of liver aging reflect partially reversible disruption of epigenetic and circadian regulatory programs, rather than exclusively irreversible molecular damage. This review focuses on two interlinked drivers: epigenetic information loss and chronosenescence, defined as age-related deterioration of circadian clock robustness. The NAD/SIRT1 axis is discussed as a central hub connecting these processes with energy metabolism. This comprehensive review synthesizes evidence from foundational studies and recent advances in single-cell multiomics, spatial transcriptomics, and CRISPR epigenetic editing technologies. It also evaluates emerging therapeutic strategies, including lifestyle intervention, NAD restoration, chronotherapy, partial cellular reprogramming, chemical reprogramming, and extracellular vesicle-based approaches, with emphasis on their current translational maturity and limitations. The integrated analysis highlights the spatial heterogeneity of liver aging and supports mechanistic links between epigenetic remodeling, circadian disruption, NAD decline, inflammation, and metabolic dysfunction. Experimental studies suggest that selected regulatory features of liver aging can be modified, but direct causal evidence in humans remains limited, and most rejuvenation-oriented strategies remain preclinical or early translational. This review establishes a unified framework for understanding liver aging as a disorder of regulatory information and temporal coordination. It provides a cautious translational roadmap for identifying modifiable nodes in liver aging while emphasizing that clinical application will require rigorous validation of safety, durability, delivery, patient selection, and long-term outcomes.
1-Naphthol Drives Liver Steatosis and Fibrosis via the CA3-CD36 Axis Independent of Obesity.
Chen R, Zeng Y, Li Y … +10 more , Hung L, Min M, Xu K, Wang J, Liu T, Deng D, Qin C, Ma J, Luo Q, Xiao X
FASEB J · 2026 Jun · PMID 42201771 · Publisher ↗
1-Naphthol (1-NAP) is a pervasive environmental pollutant and metabolite of polycyclic aromatic hydrocarbons, and the insecticide carbaryl, posing significant human health risks. Despite its recognized toxicity, the dire...
1-Naphthol (1-NAP) is a pervasive environmental pollutant and metabolite of polycyclic aromatic hydrocarbons, and the insecticide carbaryl, posing significant human health risks. Despite its recognized toxicity, the direct contribution of 1-NAP to metabolic liver disease pathogenesis remains unclear-a critical gap given the rising global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in non-obese individuals ("lean MASLD"). Here, through integrated cross-species models (zebrafish, mice, human hepatocytes), transcriptomics, and functional analyses, we demonstrate that 1-NAP directly targets hepatic carbonic anhydrase 3 (CA3). Drug affinity responsive target stability assays confirm direct 1-NAP-CA3 binding, leading to CA3 stabilization. This interaction drives transcriptional upregulation of CD36 via a CA3-dependent mechanism. Functional studies reveal that 1-NAP not only upregulates CD36 expression but also promotes its CA3-dependent translocation to the plasma membrane, resulting in enhanced CD36-mediated fatty acid uptake. This leads to hepatic steatosis and, following chronic exposure, progressive fibrosis characterized by α-SMA and Col1a1 upregulation and collagen deposition. Pharmacological inhibition of CA3 with acetazolamide reverses steatosis and injury, while dietary curcumin acting in a CD36-dependent manner ameliorates both lipid accumulation and fibrogenesis. These findings establish proof-of-concept that the CD36 node is druggable. Our work identifies the evolutionarily conserved CA3-CD36 axis as a central, targetable pathway through which an environmental pollutant drives obesity-independent MASLD, providing a mechanistic foundation for lean MASLD and advocating for the development of specific CD36 inhibitors as a therapeutic strategy.
Transcriptional Control by FOXO4 Regulates Trophoblast Differentiation and Safeguards Placental Development Through MITD1- and PCBP2-Mediated Redox Homeostasis.
Das P, Ain R
FASEB J · 2026 Jun · PMID 42201761 · Publisher ↗
Forkhead box O4 (FOXO4) is highly expressed in the placenta, but its molecular role in trophoblast biology remains unclear. Transcriptomic analysis of human placenta revealed FOXO4 abundance, prompting investigation of i...
Forkhead box O4 (FOXO4) is highly expressed in the placenta, but its molecular role in trophoblast biology remains unclear. Transcriptomic analysis of human placenta revealed FOXO4 abundance, prompting investigation of its function in trophoblast differentiation and placental development. We found that FOXO4 expression is induced during mouse trophoblast stem (TS) cell differentiation. Gain- and loss-of-function studies demonstrated that FOXO4 promotes differentiation of TS cells towards the trophoblast giant cell (TGC) lineage. Chromatin immunoprecipitation sequencing (ChIP-seq) identified FOXO4 binding to promoters of genes involved in cell cycle regulation, epigenetic modification, metabolism, and ferroptosis. Among these, MITD1 and PCBP2 emerged as key downstream effectors mediating ferroptosis resistance. FOXO4 knockdown enhanced lipid peroxidation and ferroptotic cell death, whereas FOXO4 overexpression upregulated MITD1 and PCBP2 and restored cell viability. Similar protective effects were observed in human JEG-3 trophoblast cells, indicating conservation of FOXO4's function across species. In vivo, FOXO4 expression was elevated in invasive trophoblast cells of E14.5 mouse placenta, whereas FOXO4, MITD1, PCBP2, and GPX4 were reduced in human intrauterine growth restriction (IUGR) placentae, consistent with enhanced ferroptosis. Collectively, these findings define FOXO4 as a transcriptional regulator that protects trophoblast cells from ferroptosis via MITD1 and PCBP2, thereby supporting placental development and function.
Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF-1α-Mediated Mitophagy to Inhibit Ferroptosis.
Zhao D, Chang Z, Han Q … +7 more , Wang Q, Zhai Y, Sun M, Cai D, Zhang L, Zheng X, Wang Y
FASEB J · 2026 Jun · PMID 42201682 · Publisher ↗
Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with limited pharmacological treatments. Vascular smooth muscle cell (VSMC) loss is a critical pathological feature of TAD. Roxadustat (ROX),...
Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with limited pharmacological treatments. Vascular smooth muscle cell (VSMC) loss is a critical pathological feature of TAD. Roxadustat (ROX), a HIF stabilizer for renal anemia, was evaluated in a β-aminopropionitrile (BAPN)-induced TAD mouse model. It significantly improved survival, attenuated weight loss and aortic dilation, decreased the incidence of TAD, alleviated elastic fibers damage, and ultimately inhibited TAD progression. Mechanistically, ROX upregulated HIF-1α expression, reduced vascular wall iron deposition and lipid peroxidation products (MDA, 4-HNE), and normalized aberrant expression of ferroptosis markers ACSL4, TFR1, GPX4 and FTH1. In vitro, it mitigated Erastin/Ang II-induced VSMC ferroptosis, improved mitochondrial structure and function by enhancing oxygen consumption rate (OCR), restoring membrane potential, reducing reactive oxygen species (ROS), and boosting mitophagy via upregulating HIF-1α and mitophagy markers (PINK1, Parkin). The HIF-1α inhibitor KC7F2 and siHIF-1α reversed these effects. Taken together, our findings demonstrate that ROX protects against TAD by promoting HIF-1α expression to enhance mitophagy and inhibit VSMC ferroptosis, offering potential clinical implications for TAD prevention and treatment.
NUDT21 Downregulation Promotes Liver Fibrosis by Activating the PIM2-Mediated CEBPB/SLC2A1 Glycolytic Axis in Hepatic Stellate Cells.
Xiong M, Huang S, Li Y … +1 more , Cai H
FASEB J · 2026 Jun · PMID 42201665 · Publisher ↗
Abnormal glycolysis plays a pivotal role in the activation of hepatic stellate cells (HSCs) and the progression of liver fibrosis, yet its regulatory mechanisms remain incompletely understood. This study aimed to investi...
Abnormal glycolysis plays a pivotal role in the activation of hepatic stellate cells (HSCs) and the progression of liver fibrosis, yet its regulatory mechanisms remain incompletely understood. This study aimed to investigate the role of PIM2 and its regulatory mechanisms in liver fibrosis using a CCl-induced mouse model and a TGF-β1-stimulated human HSC line (LX-2) model. The results showed that PIM2 expression was significantly upregulated in fibrotic liver tissue and a specific subset of activated HSCs. Functional experiments showed that PIM2 knockdown suppressed the activation, proliferation, and glycolysis of this specific HSC subset, whereas PIM2 overexpression promoted these processes. These effects were reversed by the glycolysis inhibitor 2-DG. Mechanistically, NUDT21 downregulation promoted PIM2 expression by regulating alternative polyadenylation (APA), resulting in PIM2 3'UTR shortening. Downstream, PIM2 activated the transcription factor CEBPB, which upregulated the transcription of the glucose transporter SLC2A1 and ultimately drove glycolysis. In line with these findings, PIM2 knockdown effectively attenuated liver fibrosis in mice. In conclusion, this study identifies PIM2 as a key driver of HSC activation and glycolysis within a distinct HSC subpopulation. PIM2 expression is regulated by NUDT21-mediated APA, and its function is mediated via the CEBPB/SLC2A1 axis, providing a potential novel therapeutic target for liver fibrosis.
Interleukin-18 in Allergic Diseases-Pathogenesis and Therapeutic Targeting.
Tian L, Li J, Hu Y … +5 more , Li M, Niu R, Su L, Zhang P, Zeng XH
FASEB J · 2026 Jun · PMID 42200718 · Publisher ↗
Allergic diseases, including pathologies such as allergic rhinitis, asthma, atopic dermatitis, and food allergies, are fundamentally driven by aberrant immunoglobulin E (IgE) production and pronounced T helper 2 (Th2) ce...
Allergic diseases, including pathologies such as allergic rhinitis, asthma, atopic dermatitis, and food allergies, are fundamentally driven by aberrant immunoglobulin E (IgE) production and pronounced T helper 2 (Th2) cell responses. The escalating global prevalence of these conditions represents a substantial public health challenge, stimulating intensive research into novel therapeutic vulnerabilities. Interleukin-18 (IL-18), a pleiotropic cytokine operating at the interface of innate and adaptive immunity, has emerged as a key modulator in this context. While classically associated with augmenting interferon-γ (IFN-γ) production by Th1 cells, IL-18 paradoxically promotes the maturation and functional potentiation of mast cells and basophils, particularly in synergy with IL-2, thereby contributing mechanistically to the immunopathology of allergic inflammation. The bioactivity of IL-18 is contingent upon proteolytic processing, and the precise molecular pathways through which it orchestrates allergic responses remain under active investigation. This review comprehensively synthesizes the current understanding of IL-18 biology, detailing its cellular origins, activation mechanisms, and intracellular signaling cascades. Furthermore, we critically evaluate the multifaceted impact of IL-18 on key immune cell subsets involved in allergic hypersensitivity and discuss the rationale and potential for therapeutic interventions targeting the IL-18 axis in the management of allergic diseases.
Uncovering Novel Landscape and Functional MicroRNA-Targets for Androgenetic Alopecia.
Chen J, Zheng C, Liu S … +9 more , Lu R, Liu W, Li K, Dai D, Wu S, Guan Q, Fan Z, Qu Q, Miao Y
FASEB J · 2026 Jun · PMID 42187542 · Publisher ↗
Androgenetic alopecia (AGA) is an inherited, androgen-driven disorder. The crucial role of microRNAs (miRNA) in hair follicle (HF) development is well known; however, a role for miRNAs in AGA pathophysiology at the molec...
Androgenetic alopecia (AGA) is an inherited, androgen-driven disorder. The crucial role of microRNAs (miRNA) in hair follicle (HF) development is well known; however, a role for miRNAs in AGA pathophysiology at the molecular level remains largely unclear. Here, we integrate miRNA with previously reported mRNA sequencing profiles, and construct specific miRNA-mRNA regulatory networks in AGA. Based on this, considerable downregulated predicted target genes of AGA bulge-containing groups were related to structure modulation, outlining the potential role of microenvironment remodeling in hair follicle stem cells (HFSCs) dysfunction in AGA. Moreover, we have established an AGA model using organ-cultured balding AGA HFs (hair follicles in the leading edge of hair recession areas in the vertex of AGA patients) to explore the role of microRNA in AGA. Using this integrative method, combined with our molecular validation data, we preliminarily describe microRNAs potentially regulating various significant pathological processes of AGA (androgen signaling, hair cycle, inflammation) and present evidence that miR-146b-5p might be capable of promoting hair growth and improving the inflammatory microenvironment in AGA HFs, presenting a promising miRNA target for AGA treatment.
Nuclear Factor Erythroid 2-Related Factor 2-Dependent Ferroptosis Suppression by Salvianolic Acid B Preserves Microvascular Integrity and Reduces Risk Factors for Hemorrhagic Transformation After Cerebral Infarction.
Liang J, Zhao X, Xiong R … +2 more , Zhang X, Wang R
FASEB J · 2026 May · PMID 42186809 · Publisher ↗
This study aimed to elucidate the mechanism by which salvianolic acid B (Sal B) protects against reperfusion-induced vascular damage following cerebral infarction, specifically investigating its role in preserving microv...
This study aimed to elucidate the mechanism by which salvianolic acid B (Sal B) protects against reperfusion-induced vascular damage following cerebral infarction, specifically investigating its role in preserving microvascular integrity through the ACSL4/Nrf2 axis-mediated inhibition of ferroptosis. A mouse model of cerebral ischemia/reperfusion injury was established via middle cerebral artery occlusion (MCAO). Mice were divided into Sham, MCAO, MCAO+Sal B, and MCAO+Sal B + ML385 (Nrf2 inhibitor) groups. We employed RNA sequencing, TTC staining, behavioral tests, histopathology, and molecular biology techniques to assess infarct volume, neurological function, ferroptosis markers (ACSL4, GPX4, TFR1), iron deposition, oxidative stress, inflammation, and Nrf2 pathway activity. Sal B markedly reduced infarct volume and improved neurological outcomes. At the mechanistic level, Sal B suppressed pro-ferroptotic mediators ACSL4 and TFR1 while enhancing Nrf2 nuclear translocation and upregulating its downstream effectors HO-1 and GPX4. These changes were associated with decreased iron deposition, reduced lipid peroxidation, and alleviated neuroinflammation. Importantly, pharmacological inhibition of Nrf2 with ML385 largely abolished these protective effects, underscoring the central role of Nrf2 signaling. Sal B alleviates reperfusion-associated damage post-cerebral infarction by synergistically downregulating the pro-ferroptotic gene ACSL4 and activating the Nrf2/HO-1 antioxidant pathway, thereby cooperatively inhibiting ferroptosis, preserving BBB integrity, and reducing neuronal injury.
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