FASEB Journal[JOURNAL]
Sun
200 papers
Ferroptosis as a Nexus in Skeletal Muscle Pathophysiology: From Molecular Networks to Precision Medicine.
Ji Y, Qi L, Sun J … +3 more , Wang J, Shang T, Sun H
FASEB J · 2026 May · PMID 42172442 · Publisher ↗
Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is a central pathological mechanism unifying diverse skeletal muscle disorders, including atrophy (e.g., sarcopenia, CKD), impaired regeneration, an...
Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is a central pathological mechanism unifying diverse skeletal muscle disorders, including atrophy (e.g., sarcopenia, CKD), impaired regeneration, and acute injury. This review synthesizes recent evidence to map a multilayered regulatory network encompassing dysregulated iron/lipid metabolism, collapsed antioxidant defenses (e.g., GPX4, FSP1, GCH1), organelle cross-talk, and complex signaling pathways (e.g., NRF2, p53). Critical translational gaps persist, such as a lack of human validation, insufficient understanding of context-dependent regulation, and challenges in biomarker development. Future directions must prioritize human biomarker discovery, elucidate nonautonomous drivers (e.g., senescent macrophages), evaluate organelle-targeted therapies, and advance biomarker-stratified trials with repurposed drugs (e.g., SGLT2 inhibitors) to enable ferroptosis-targeted precision medicine for muscle diseases.
Ac-SDKP Attenuates Silica-Induced Pulmonary Fibrosis by Inhibiting ALKBH1-Mediated mA Demethylation of miR-129-5p.
Li Q, Du J, Yi X … +17 more , Li S, Yang Y, Wang X, Xu Z, Jin F, Li T, Li Y, Xu D, Wei Z, Cai W, Mao N, Zhang L, Yu X, Shi Y, Yang F, Xu H, Gao X
FASEB J · 2026 May · PMID 42172441 · Publisher ↗
Silicosis, one of the most common and severe forms of pneumoconiosis, remains a major occupational health concern worldwide. Given the lack of effective therapies, understanding the underlying molecular mechanisms is urg...
Silicosis, one of the most common and severe forms of pneumoconiosis, remains a major occupational health concern worldwide. Given the lack of effective therapies, understanding the underlying molecular mechanisms is urgently needed. Here, we report that ALKB homolog 1 (ALKBH1), an N6-methyladenosine (mA) demethylase, is upregulated in silica-induced pulmonary fibrosis and plays a pro-fibrotic role. The antifibrotic peptide Ac-SDKP inhibited Alkbh1 expression and alleviated pulmonary fibrosis. Mechanistically, ALKBH1 suppressed the biosynthesis of miR-129-5p by removing mA modification from pri-miR-129-5p, thereby reducing DGCR8-mediated processing and leading to decreased mature miR-129-5p levels. Ac-SDKP reversed this process, restoring miR-129-5p expression. Functionally, overexpression of miR-129-5p attenuated silica-induced pulmonary fibrosis by suppressing macrophage activation. Collectively, these findings identify the Ac-SDKP-ALKBH1-miR-129-5p axis as a critical regulatory mechanism, with ALKBH1-mediated mA demethylation of pri-miR-129-5p representing a key node and a promising therapeutic target for silicosis.
The Cellular Response Capacity as Diagnostic Head Start in Neutrophil Endotoxemia Sensing.
Messerer DAC, Mohamed AOK, Wohlgemuth L … +11 more , Vidoni L, Knapp CL, Müller P, Thomaß BD, Föhr K, Barth E, Weiss M, Jungwirth B, Nilsson Ekdahl K, Nilsson B, Huber-Lang M
FASEB J · 2026 May · PMID 42172439 · Publisher ↗
Early detection of endotoxemia-related systemic inflammation remains a major unmet diagnostic need. Established inflammatory biomarkers largely reflect downstream protein biosynthesis and therefore rise with delay. Direc...
Early detection of endotoxemia-related systemic inflammation remains a major unmet diagnostic need. Established inflammatory biomarkers largely reflect downstream protein biosynthesis and therefore rise with delay. Direct monitoring of rapid leukocyte phenotype changes, particularly in neutrophils, may provide an earlier readout, but insufficient standardization has limited clinical translation. Using flow cytometry, we established the neutrophil cellular response capacity (CRC) in a controlled ex vivo human whole-blood model of endotoxemia employing intact lipopolysaccharide (LPS) as a defined prototypical pathogen-associated molecular pattern. The performance of the neutrophil CRC was thoroughly characterized and compared to conventional humoral inflammatory markers with respect to their ability to detect endotoxemia. Screening identified CD10, CD11b, and CD66b as the best-performing CRC markers, detecting prior LPS exposure at concentrations in the low pg/mL range. In the dynamic continuum of inflammation, encompassing cellular phenotype shifts, functional changes, and subsequent humoral response, the CRC of neutrophils reliably detected very early phenotypic alterations, surpassing the sensitivity of classical clinical inflammation markers in our human blood endotoxemia model. In summary, the CRC represents a proof-of-concept approach for standardized early cellular immunomonitoring in ex vivo endotoxemia. Further evaluation in more heterogeneous inflammatory settings and in patients with systemic inflammation or sepsis is warranted.
Mitochondrial-Haplotype Influences Plasma Metabolome, Lipidome, and Proteome in a Sex Specific Manner in the Genetically Heterogenous OKC-HET Rat.
Nguyen HVM, Hu F, Shakya E … +11 more , Fender C, Lee K, Schindler J, Garcia-Jaramillo M, Ahsan N, Siebert JC, Borengasser SJ, Hord NG, Stout MB, Austad S, Richardson A
FASEB J · 2026 May · PMID 42171346 · Publisher ↗
The effect of mitochondrial-haplotype (mt-haplotype) on aging was studied using a unique rat model (OKC-HET), which has a heterogenous nuclear background combined with mitochondria from either Brown Norway (B-haplotype)...
The effect of mitochondrial-haplotype (mt-haplotype) on aging was studied using a unique rat model (OKC-HET), which has a heterogenous nuclear background combined with mitochondria from either Brown Norway (B-haplotype) or Wistar Kyoto (W-haplotype) rats that differ in 94 nucleotides. The impact of mt-haplotype on aging was studied using an unbiased multi-omics approach to analyze the plasma from 9- and 26-month-old male and female OKC-HET rats. Of the 280 metabolites, 961 lipids, and 230 proteins that were different in each age group, 50%-80% were mt-haplotype specific, occurring in either OKC-HET or OKC-HET rats but not both. The majority (78%-93%) of the differences that were mt-haplotype specific were also sex specific, occurring in either male or female rats but not both. Our data are the first to show the potential importance of mt-haplotype in aging and that this mt-haplotype difference is largely sex dependent.
CircCOG6 Suppresses Proliferation and Differentiation of Chicken Chondrocytes in Tibial Dyschondroplasia by Targeting ACVRL1 Protein.
Ji X, Hu Z, Xu H … +7 more , Lu Y, Chen J, Zhu J, Guo L, Wang X, Liu Y, Wang Y
FASEB J · 2026 May · PMID 42171326 · Publisher ↗
Tibial dyschondroplasia (TD) is a chronic cartilage disorder commonly found in fast-growing broiler chickens, characterized by impaired tibial development and subsequent growth retardation, which collectively compromise...
Tibial dyschondroplasia (TD) is a chronic cartilage disorder commonly found in fast-growing broiler chickens, characterized by impaired tibial development and subsequent growth retardation, which collectively compromise poultry health and production efficiency. Circular RNAs (circRNAs), a class of non-coding RNAs with covalently closed loop structures, have recently garnered increasing attention in biological research. Growing evidence suggests that circRNAs are involved in the fine-tuned regulation of TD in broiler through competitive endogenous RNA (ceRNA) networks. However, the role of circRNA in TD pathogenesis via protein-binding mechanisms remains unclear. In our previous study, we identified circCOG6 (circ_0002951), a circular RNA derived from the COG6 gene, as significantly upregulated in a Thiram-induced TD model, indicating its potential critical role in TD onset and progression. In vitro functional assays revealed that overexpression of circCOG6 suppresses proliferation and differentiation of TD chondrocytes and promotes apoptosis. Mechanistically, through AGO2-RIP, RNA pull-down, and RIP experiments, we demonstrated that circCOG6 interacts with activin receptor type-1-like (ACVRL1) to inhibit chondrocyte proliferation and differentiation, promote apoptosis, and synergistically enhance BMP/Smad signaling activation, thereby contributing to TD pathogenesis. Furthermore, in vivo studies showed that intra-articular injection of adeno-associated virus carrying shRNA targeting circCOG6 (AAV-sh-circCOG6) alleviates TD lesions in a broiler chicken. In conclusion, this study is the first to elucidate a circRNA-mediated regulatory mechanism in broiler TD via RBP-binding protein interaction, thereby enriching the TD regulatory network and offering a potential therapeutic target for its treatment.
Ribotoxic Stress Response: Coordinating Pyroptosis and Apoptosis.
Sun J, Zhang Y, Yan L … +3 more , Yao J, Hu J, Feng X
FASEB J · 2026 May · PMID 42166212 · Publisher ↗
Ribotoxic stress response (RSR) is a translation-linked stress pathway that emerges when ribosomes stall and collide. Its upstream trigger is the MAP3K/ZAKα, a leucine-zipper- and SAM-containing kinase that relays riboto...
Ribotoxic stress response (RSR) is a translation-linked stress pathway that emerges when ribosomes stall and collide. Its upstream trigger is the MAP3K/ZAKα, a leucine-zipper- and SAM-containing kinase that relays ribotoxic stress to downstream programs shaping metabolism, immune signaling, and cell-fate decisions. Increasing evidence suggests that RSR also connects two major forms of programmed cell death-apoptosis and pyroptosis-by coordinating signaling crosstalk that shapes death outcomes. Disruption of this regulatory axis is associated with chronic inflammatory disorders, immune dysfunction, and malignancy. Here, we summarize current knowledge on the molecular mechanisms through which RSR interfaces with apoptotic and pyroptotic pathways, and we discuss its roles in cellular homeostasis and disease. Clarifying how RSR regulates cell-death signaling could guide the development of targeted therapeutic strategies for conditions involving dysregulated inflammation and cell death.
Nesfatin-1 Ameliorates Acute Pancreatitis by Inhibiting the Pyroptosis of Acinar Cells and Inflammation Mediated by Macrophages and Neutrophils.
Li H, Wang X, Niu Y … +4 more , Sun L, Yang Y, Zhang W, Yin Y
FASEB J · 2026 May · PMID 42165421 · Publisher ↗
Acute pancreatitis (AP) is an inflammatory disorder with no efficient therapy. Here we demonstrate that the anorexigenic peptide nesfatin-1 exerts potent and dose-dependent protection against both caerulein-induced and h...
Acute pancreatitis (AP) is an inflammatory disorder with no efficient therapy. Here we demonstrate that the anorexigenic peptide nesfatin-1 exerts potent and dose-dependent protection against both caerulein-induced and hypertriglyceridemic AP. Intraperitoneal administration of nesfatin-1 to restore its serum levels significantly reduced pancreatic necrosis, edema, and infiltration of immune cells, as well as circulating levels of amylase, lipase, and pro-inflammatory cytokines. RNA-seq revealed that nesfatin-1 down-regulated the ER-stress signature (Ddit3, Atf3, Ppp1r15a) and the NF-κB/NLRP3 signaling. Further studies in primary acinar cells confirmed that nesfatin-1 at the dose of 10 nM suppressed phosphorylated eIF2α, DDIT3, ATF3, p65, and NLRP3, thereby inhibiting pyroptosis. Consequently, nesfatin-1 attenuated macrophage/neutrophil infiltration, shifted M1 toward M2 macrophages, inhibited the release of inflammatory cytokines, and alleviated multi-organ injury in lung, intestine, and spleen. Collectively, nesfatin-1 limits AP severity by restraining ER-stress-driven pyroptosis and innate immune activation. Thus, nesfatin-1 may serve as a promising therapeutic candidate for acute pancreatitis.
OPA1 in MC4R Neurons Regulates Dietary Fat Intake and Body Weight in Mice.
Matsumura S, Fujiwara M, Horie S … +8 more , Marutani M, Nousou E, Iki N, Yamato Y, Otonashi Y, Sasaki T, Fujitani M, Fujikawa T
FASEB J · 2026 May · PMID 42165391 · Publisher ↗
Melanocortin 4 receptor (MC4R) neurons in the hypothalamus regulate appetite and energy balance, and mitochondrial dynamics are important for neuronal function. However, how dietary fat intake affects mitochondrial regul...
Melanocortin 4 receptor (MC4R) neurons in the hypothalamus regulate appetite and energy balance, and mitochondrial dynamics are important for neuronal function. However, how dietary fat intake affects mitochondrial regulation in the hypothalamus has not been fully clarified. Here we examined the effects of soybean oil intake on hypothalamic mitochondrial gene expression and generated MC4R neuron-specific mitochondrial fusion factor OPA1 (Optic atrophy-1) knockout mice. Voluntary ingestion of soybean oil increased hypothalamic OPA1 expression in wild-type male mice but not in female mice. In contrast, loss of OPA1 in MC4R neurons led to elevated soybean oil consumption and progressive obesity, with a more pronounced obesity phenotype in females. MC4R agonist administration suppressed food intake, but this effect was attenuated specifically in female knockout mice. Together, these results suggest that OPA1 in MC4R neurons is involved in the response to dietary fat intake and contributes to the control of feeding and body weight, with clear differences between males and females. This study provides new insight into how mitochondrial function in the hypothalamus is linked to energy metabolism under conditions of dietary fat intake.
ProS/Mer Alleviates Sepsis-Induced Neuromuscular Dysfunction by Inhibiting TLR4/MyD88/NF-κB Signals.
Wang S, Yang Y, Sun J … +6 more , Yan B, Li T, Wen L, Zhang H, Shu J, Xie F
FASEB J · 2026 May · PMID 42165373 · Publisher ↗
Sepsis frequently leads to profound neuromuscular dysfunction, in part driven by spinal neuroinflammation. The receptor tyrosine kinase Mer is a key regulator of immune homeostasis, yet its role in sepsis-induced neuromu...
Sepsis frequently leads to profound neuromuscular dysfunction, in part driven by spinal neuroinflammation. The receptor tyrosine kinase Mer is a key regulator of immune homeostasis, yet its role in sepsis-induced neuromuscular impairment remains unclear. This study investigated the contribution of Mer signaling to spinal neuroinflammation and neuromuscular dysfunction in sepsis. Sepsis was induced in rats using the cecal ligation and puncture (CLP) model. Neuromuscular function was assessed by muscle mass analysis, compound muscle action potential (CMAP) recordings, and nerve conduction studies. Neuronal survival and neuromuscular junction (NMJ) integrity were evaluated histologically. Spinal inflammatory responses and signaling pathways were analyzed by measuring cytokine levels, microglial activation, and expression of TLR4/MyD88/NF-κB and STAT1/SOCS pathway components. To assess therapeutic potential, the Mer ligand Protein S (ProS) was administered intrathecally in both wild-type (WT) and Mer-deficient (Mer) rats. Mer deficiency significantly aggravated sepsis-induced muscle wasting, reduced CMAP amplitude, prolonged latency, impaired motor conduction velocity, increased neuronal loss, and exacerbated NMJ disintegration. These functional impairments were associated with elevated spinal IL-6 and TNF-α levels, enhanced microglia/macrophage activation, upregulated TLR4/MyD88/NF-κB signaling, and suppressed STAT1/SOCS pathway activation. Intrathecal ProS treatment markedly improved neuromuscular performance, attenuated spinal inflammatory responses, and restored neuronal integrity and NMJ structure in both WT and Mer CLP rats. ProS/Mer signaling plays a critical protective role in sepsis-induced neuromuscular dysfunction by suppressing pro-inflammatory pathways and activating anti-inflammatory STAT1/SOCS signaling in the spinal cord. Therapeutic targeting of the ProS/Mer axis may represent a promising strategy for the treatment of sepsis-associated neuromyopathy.
Plasminogen Activator Inhibitor-1 is Internalized by Endothelial Cells via A Pinocytosis-Like Mechanism and Evades Degradation.
McAdow M, Ahmetaj G, Hauschel R … +2 more , Eichmann A, Sessa W
FASEB J · 2026 May · PMID 42165362 · Full text
Plasminogen activator inhibitor 1 (PAI1) is a secreted protease inhibitor, but accumulating evidence supports a role for PAI1 in regulating intracellular processes. PAI1 is secreted in an active conformation that serves...
Plasminogen activator inhibitor 1 (PAI1) is a secreted protease inhibitor, but accumulating evidence supports a role for PAI1 in regulating intracellular processes. PAI1 is secreted in an active conformation that serves as a bait for plasminogen activators (PA). Interaction between PAs and PAI1 results in a covalent linkage. PAI1/PA bind LRP1 and uPAR on the cell surface, triggering internalization and degradation. However, it was recently shown that exogenous PAI1 directly interacts with endothelial nitric oxide synthase inside endothelial cells. Our objective was to characterize the non-degradative pathway for PAI1 internalization. We use a hemagglutinin (HA)-tagged construct of PAI1 to track endocytosis of exogenous PAI1 in cultured endothelial cells via Western blotting of cell lysates and immunofluorescence microscopy. We demonstrate that PAI1-HA is actively internalized through a non-receptor-mediated mechanism, independent of clathrin-mediated endocytosis or caveolae. PAI1-HA internalization was partially inhibited by a derivative of amiloride, an inhibitor of macropinocytosis, though it was independent of Rac1 and CDC42, GTPases used for macropinocytosis. After internalization, PAI1-HA evades degradation for at least 3 h. By contrast, PAI1/uPA is degraded within 30 min of internalization. PAI1-HA internalization is independent of LRP1 and uPAR. We propose a model whereby PAI1/PA is endocytosed by LRP1- and uPAR-dependent endocytosis, whereas latent PAI can be internalized through a pinocytic-like mechanism and evade degradation, facilitating paracrine signaling.
High Relevance of Fatty Acid Oxidation in a Migrating Mammal, the Nathusius' Pipistrelle (Pipistrellus nathusii).
Walker A, Truong TT, Klingenspor M … +5 more , Hedenström A, Pētersons G, Schmitt-Kopplin P, Currie SE, Voigt CC
FASEB J · 2026 May · PMID 42165356 · Publisher ↗
Bats are the only mammals capable of powered flight, allowing them to cover relatively long distances in a short time. However, the general inability of mammals to fuel endurance exercise solely by oxidizing fatty acids...
Bats are the only mammals capable of powered flight, allowing them to cover relatively long distances in a short time. However, the general inability of mammals to fuel endurance exercise solely by oxidizing fatty acids may prevent bats from undertaking long-distance intercontinental migrations-like birds do. Here, we conducted untargeted metabolomics to reveal the oxidative fuels used by wild caught Nathusius' pipistrelles. We investigated polar metabolites and lipids in whole blood from bats flying under controlled wind tunnel or field conditions and how metabolites respond to the physiological challenge. Around 70% of detected acyl carnitines were significantly elevated after flight in the wind tunnel compared to resting bats. The phospholipid levels varied; some increased while others decreased significantly after flight, and most did not return to resting levels within 1 h of recovery. During migration season, we observed a significant increase of phosphatidylethanolamines with unsaturated fatty acids and a bulk increase of several phosphatidylcholines and their lyso-derivatives. While migration had a clear effect on phospholipids, recovering after flight in both seasons was less pronounced and only 24% of acyl carnitines were increased after 1 h of rest. We conclude that endurance exercise such as migration has a greater influence on lipid composition and their abundance than short flights, which indicates a relatively high relevance of fatty acid oxidation to fuel migration in bats.
Molecular Mechanism of NSUN6-Mediated Epigenetic Modifications in the Malignant Progression of Colorectal Cancer Cells.
Dong Z, Wang Y, Chen J … +4 more , Yu W, Chen Y, Peng W, Cheng W
FASEB J · 2026 May · PMID 42165352 · Publisher ↗
Colorectal cancer (CRC) stands as a widespread gastrointestinal malignancy, marked by high morbidity and mortality, and poses a substantial threat to global public health. This research aims to explain the significance o...
Colorectal cancer (CRC) stands as a widespread gastrointestinal malignancy, marked by high morbidity and mortality, and poses a substantial threat to global public health. This research aims to explain the significance of NSUN6 in CRC progression. Tumor tissues were harvested from CRC patients, with subsequent analysis of the association between NSUN6 expression and clinical features. After intervening in NSUN6 expression in CRC cells and normal cells, cell proliferation, apoptosis, migration, and invasion were detected. m5C modification and ALYREF enrichment on KLF1 were analyzed. The binding of KLF1 to USP15 was detected. We found that NSUN6 expression was increased and correlated with the clinical characteristics of CRC patients. After downregulation of NSUN6, cell proliferation was decreased, apoptosis was increased, and cell migration and invasion were reduced. NSUN6 stabilizes KLF1 mRNA via ALYREF-dependent m5C modification, thereby enhancing KLF1 expression. KLF1 promotes USP15 expression. Overexpression of KLF1 or USP15 alleviated the suppressing effect of NSUN6 downregulation on the malignant progression of CRC cells. NSUN6 downregulation inhibited tumor growth and liver/lung metastasis, which were promoted upon KLF1 overexpression. In conclusion, NSUN6 mediates m5C modification and promotes the malignant progression of CRC cells via the KLF1/USP15 axis.
Loss of Striatal Bradykinin B2 Receptor Alters Anxiety and Motivational Behaviors in Male Mice.
Tavares MR, Araujo RC, Martins MG … +3 more , Donato J, Bader M, Wasinski F
FASEB J · 2026 May · PMID 42165346 · Publisher ↗
The kallikrein-kinin system (KKS) has been extensively studied in peripheral tissues, but its role in the central nervous system (CNS) remains poorly understood. The bradykinin B2 receptor (B2R) is constitutively express...
The kallikrein-kinin system (KKS) has been extensively studied in peripheral tissues, but its role in the central nervous system (CNS) remains poorly understood. The bradykinin B2 receptor (B2R) is constitutively expressed in the brain, where it may modulate neuronal differentiation, neuroplasticity, and behavioral aspects. Here, we investigated the functional role of striatal B2R by conditionally deleting the Bdkrb2 gene in the dorsal striatum of adult male mice (Bdkrb2) using bilateral stereotaxic injections of an AAV8 that induces Cre and tdTomato expression. Mice lacking B2R in the dorsal striatum displayed several context-dependent behavioral alterations, such as reduced anxiety-like behavior and decreased sucrose preference. Moreover, these animals showed enhanced voluntary wheel running, suggesting alterations in motivation-related behavioral output. Immunofluorescence analysis revealed that among dTomato-positive neurons, approximately 17% co-expressed DARPP-32, indicating that a subset of the transduced cells corresponds to dopaminoceptive medium spiny neurons. Together, these findings show that dorsal striatal B2R deletion alters anxiety-related and motivational/hedonic behaviors in male mice and suggest that these effects may involve striatal neuronal populations, including a subset of dopaminoceptive neurons.
Targeting DNMT1 Attenuates Radiation-Induced Heart Disease: An Integrated Multiomic and Functional Study.
Wang G, Li YL, Wang BW … +8 more , Wang R, Wang Y, Shu YB, Zhang WB, Wu P, Hu YJ, Lu WJ, Xie P
FASEB J · 2026 May · PMID 42165283 · Publisher ↗
Radiation-induced heart disease (RIHD) is a serious adverse reaction after tumor radiotherapy; its molecular mechanism is not yet clear, and there is a lack of effective treatment strategies. DNA methyltransferase 1 (DNM...
Radiation-induced heart disease (RIHD) is a serious adverse reaction after tumor radiotherapy; its molecular mechanism is not yet clear, and there is a lack of effective treatment strategies. DNA methyltransferase 1 (DNMT1) plays crucial roles in various biological processes, but its function in RIHD remains to be explored. This study aimed to systematically elucidate the molecular map of RIHD using multiomic methods, with a focus on the specific functions and mechanisms of DNMT1 in the development of RIHD. In this study, in vivo and in vitro models of radiation-induced cardiac injury were constructed. Changes in molecular expression in cardiac tissues and cells caused by radiation were systematically analyzed through techniques such as transcriptomics and proteomics. Adeno-associated virus and lentivirus transfection techniques were used to knock down Dnmt1 expression to explore its functional role in RIHD. Multiomic analysis revealed significant activation of immune/inflammatory responses and metabolic disorders in RIHD. X-ray irradiation induced myocardial tissue and cell damage and inhibited PI3K/PDK1/AKT signaling. Moreover, radiation significantly upregulated the expression of DNMT1 in myocardial tissue and cells. Dnmt1 knockdown alleviated radiation-induced myocardial tissue and cell damage and partially reversed the inhibition of PI3K/AKT signaling. In addition, 15 proteins directly interacting with DNMT1 were identified by CO-IP and GST-pulldown assays combined with mass spectrometry, suggesting that these proteins may participate in the development of RIHD through a variety of molecular mechanisms. The results of this study revealed that DNMT1 plays a role in promoting disease progression by regulating the PI3K/AKT signaling pathway in RIHD. These findings provide a new perspective for understanding the pathogenesis of RIHD and suggest that DNMT1 may serve as a potential target for therapeutic interventions. Therefore, DNMT1 represents a promising therapeutic target for preventing RIHD.
NME3 Interacts With NAA10 to Promote RUNX2 Nuclear Translocation and Odontogenic Differentiation in Human Dental Pulp Stem Cells.
Fan C, Xu K, Fei W … +3 more , Li Y, Zhao S, Ju Y
FASEB J · 2026 May · PMID 42165278 · Publisher ↗
Human dental pulp stem cells (hDPSCs) hold great promise for dental tissue regeneration, yet the molecular mechanisms underlying their odontogenic differentiation remain unclear. This study investigates the role of nucle...
Human dental pulp stem cells (hDPSCs) hold great promise for dental tissue regeneration, yet the molecular mechanisms underlying their odontogenic differentiation remain unclear. This study investigates the role of nucleoside diphosphate kinase 3 (NME3) in regulating hDPSC differentiation. NME3 was found to be specifically expressed in odontoblasts of rat tooth germs and positively associated with odontogenic markers (DSPP, DMP1, and RUNX2) in hDPSCs. Functional assays revealed that NME3 promotes odontogenic differentiation, while its knockdown suppresses mineralization and marker expression. Mass spectrometry identified N-α-acetyltransferase 10 (NAA10) as a potential NME3-interacting protein, with both showing colocalization in hDPSCs and developing odontoblasts. Mechanistically, NAA10 knockdown rescued the differentiation deficits caused by NME3 silencing, and NAA10 overexpression attenuated the effects of NME3. Moreover, NME3 appears to facilitate the nuclear translocation of RUNX2, a key transcription factor in odontogenesis. These findings suggest that NME3 may regulate hDPSC odontogenic differentiation through interaction with NAA10 and modulation of RUNX2 localization, offering new insights into the molecular control of dental tissue regeneration.
Regulation of Satellite Cells and Myogenesis in Response to Eccentric Resistance Exercise in Hypoxic Conditions in Healthy Young Men.
van Doorslaer de Ten Ryen S, Warnier G, Antoine N … +5 more , Boyer E, Kienlen-Campard P, Copine S, Francaux M, Deldicque L
FASEB J · 2026 May · PMID 42165230 · Publisher ↗
Satellite cells participate in myogenesis and contribute to skeletal muscle regeneration and hypertrophy. Amongst other stimuli, satellite cells can be activated by exercise and hypoxia. However, the cumulative effect of...
Satellite cells participate in myogenesis and contribute to skeletal muscle regeneration and hypertrophy. Amongst other stimuli, satellite cells can be activated by exercise and hypoxia. However, the cumulative effect of exercise on hypoxia on myogenesis is not well understood, certainly in humans. Furthermore, whether satellite cell activation and myogenesis differ between environmental hypoxia and blood flow restriction is not known. The purpose of this study was to analyze satellite cell and myogenic markers in response to acute eccentric resistance exercise in normoxia, normobaric environmental hypoxia, and with blood flow restriction (local hypoxia). Thirty-eight healthy young men were allocated to one of the three experimental conditions: normoxia (n = 13), normobaric environmental hypoxia (n = 12), and blood flow restriction (n = 13). They all performed 5 series of 15 repetitions at 60°/s for the knee extension and 30°/s for the knee flexion on an isokinetic dynamometer. Vastus lateralis muscle biopsies and blood samples were taken before, 1, 24, and 72 h after exercise. Myogenic regulatory factor expression was upregulated after exercise similarly in the normoxic and hypoxic groups and attenuated in the blood flow restriction group. Despite differential regulation of myogenic regulatory factor expression and circulating creatine kinase levels after eccentric resistance exercise, none of the investigated hypoxia markers and immediate early genes, inflammatory markers, growth factors, except insulin-like growth factor-1, and mitogen-activated protein kinase members were differently regulated between the groups. Contrary to our hypothesis, satellite cell activation and myogenesis were not potentiated by the combination of eccentric resistance exercise and hypoxic conditions.
Myeloid ATF3 Protects Against Liver Fibrosis by Modulating the Extracellular Microenvironment and Macrophage Inflammatory Signaling.
Ling H, Hu Y, Onyuru J … +12 more , Shi J, Steffani M, Wang J, Wasmaier L, Schulze S, Märitz N, Xin Z, Friess H, Holzmann B, Hüser N, Stoess C, Hartmann D
FASEB J · 2026 May · PMID 42160137 · Publisher ↗
Activating transcription factor 3 (ATF3) is a stress-inducible transcription factor that regulates inflammatory responses; however, its cell-type-specific role in liver fibrosis remains incompletely defined. We investiga...
Activating transcription factor 3 (ATF3) is a stress-inducible transcription factor that regulates inflammatory responses; however, its cell-type-specific role in liver fibrosis remains incompletely defined. We investigated the function of myeloid cell-specific ATF3 in carbon tetrachloride (CCl)-induced liver fibrosis. ATF3 induction was confirmed in bone marrow-derived macrophages following lipopolysaccharide stimulation in vitro. Myeloid-specific Atf3 knockout mice (Atf3 LysM-Cre+) and littermate controls were subjected to CCl treatment to determine the impact of ATF3 loss in vivo. Myeloid ATF3 deficiency significantly exacerbated CCl-induced liver injury, reflected by elevated serum ALT and AST levels, increased collagen deposition, and higher fibrosis scores. ATF3 loss enhanced hepatic stellate cell activation, as evidenced by increased α-SMA protein and elevated Acta2 and Col1a1 expression. Although total macrophage abundance was unchanged, ATF3 deficiency shifted macrophage composition toward increased Ly6C+ infiltrating monocyte-derived macrophages and reduced Kupffer cell markers. Mechanistically, Atf3-deficient livers displayed increased inflammatory chemokine expression (Ccl3, Ccl4, Ccl5, Ccl8), reduced matrix metalloproteinases (Mmp2, Mmp8, and Mmp9), increased tissue inhibitor of metalloproteinases 1 (Timp1), and enhanced activation of transforming growth factor-beta1 (TGF-β1)/SMAD signaling. These findings identify myeloid ATF3 as a protective regulator that restrains inflammatory amplification and extracellular matrix accumulation during liver fibrosis. Modulation of ATF3-dependent pathways may represent a potential therapeutic strategy for fibrotic liver disease.
Deletion of Plasmodium yoelii Merozoite Surface Protein 8 Protects Mice From Lethal Blood-Stage Malaria and Is Associated With Enhanced Splenic CCL19-CCR7 Signaling.
Sun Y, Fan Z, Ge J … +10 more , Cui W, Zuo S, Tan L, Han S, Yan Y, Wang B, Cao J, Lv Z, Zhu G, Cheng Y
FASEB J · 2026 May · PMID 42160130 · Publisher ↗
Merozoite surface protein 8 (MSP8) is a conserved blood-stage antigen implicated in erythrocyte invasion and vaccine-induced protection, but its role in coordinating host immunity during malaria remains unclear. Here, we...
Merozoite surface protein 8 (MSP8) is a conserved blood-stage antigen implicated in erythrocyte invasion and vaccine-induced protection, but its role in coordinating host immunity during malaria remains unclear. Here, we combined MSP8 immunization, CRISPR/Cas9-mediated deletion of Plasmodium yoelii (P. yoelii) msp8, and perturbation of chemokine-receptor signaling to define how MSP8 shapes disease outcome in the lethal murine model of malaria. Mouse antisera against Plasmodium falciparum MSP8 partially inhibited merozoite invasion of human erythrocytes in vitro, and PyMSP8 immunization conferred partial protection against lethal P. yoelii 17XL challenge, supporting the notion that MSP8 functions both as an invasion-related antigen and as a target of the protective immune responses. A full-length pymsp8 knockout line (P. yoelii 17XL ΔMSP8) was generated successfully and ΔMSP8 strain infected mice exhibited reduced peak parasitemia, attenuated splenomegaly, and a self-resolving course. Transcriptomic, immunoblot, and immunohistochemical analyses revealed MSP8 deficiency upregulated chemokine CCL19 and preserved its receptor CCR7 in the spleen of infected mice, accompanied by increased IFN-γ level in spleen and serum. Functional knockdown of CCR7 using adeno-associated virus (AAV)-delivered shRNA partially abrogated the survival advantage of ΔMSP8 infection, lowered splenic CCR7 and IFN-γ levels and increased the mortality. Together, these data support a model in which parasite-expressed MSP8 is associated with reduced activity of a splenic CCL19-CCR7 axis that inducing IFN-γ-driven protective responses, whereas loss of MSP8 preserves and enhances this chemokine pathway and converts otherwise lethal infection into a self-resolving outcome. Targeting MSP8 or therapeutically augmenting CCL19-CCR7 signaling therefore represent complementary strategies for malaria vaccines and host-directed interventions.
Neuregulin-1 Mitigates Kidney Injury in Humanized Sickle Cell Mice.
Agbozo WK, Solomon W, Erskine IJ … +10 more , Lekpor CE, Babayewa O, Bashi A, Harbuzariu A, Asberry A, Adel D, Adjei S, Paemka L, Ofori-Acquah SF, Stiles JK
FASEB J · 2026 May · PMID 42160023 · Publisher ↗
Sickle cell disease (SCD) is characterized by chronic hemolysis, inflammation, and progressive kidney injury which leads to renal failure and increased mortality rates with limited therapeutic options available. Neuregul...
Sickle cell disease (SCD) is characterized by chronic hemolysis, inflammation, and progressive kidney injury which leads to renal failure and increased mortality rates with limited therapeutic options available. Neuregulin-1 (NRG-1) is a cytoprotective growth factor with anti-inflammatory and antioxidant properties and an established clinical safety profile in humans. Using Townes humanized sickle cell (HbSS) mice, we investigated whether NRG-1 mitigates kidney injury by reducing hemolytic and inflammatory mediators and enhancing renal cytoprotective and repair factors. NRG-1 treatment reduced plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines levels, while increasing the proportion of circulating fetal hemoglobin-containing red blood cells (F-cells). Treatment mitigated urinary cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) elevations and improved renal histopathology, including reduced iron deposition, glomerular congestion, and sclerosis. NRG-1 also enhanced heme oxygenase-1 (HO-1) expression in HbSS kidneys and increased urinary renal repair biomarkers clusterin and epidermal growth factor (EGF). Collectively, these findings provide new mechanistic insight supporting further exploration of NRG-1 as a therapeutic agent for mitigating kidney injury in SCD.
Dual Knockout Models of the Spatially and Functionally Conserved rgra and rgrb Zebrafish Genes Reveal the Requirement of RGR for the Integrity of Cone-Mediated Photopic Vision, the Photopic Visual Cycle and Bruch's Membrane Morphology.
Ruddin G, McCann T, Kaylor JJ … +11 more , Fox MM, Fehilly JD, Ward R, Faulkner A, Moran AL, Wynne K, Radu RA, Monaghan MG, Thorpe SD, Travis GH, Kennedy BN
FASEB J · 2026 May · PMID 42160018 · Publisher ↗
The retinal G protein-coupled receptor (RGR) is a visual cycle photoisomerase that photopically regenerates 11-cis-retinal (11cRAL). It plays a crucial role in sustaining vision. Here, we investigated the in vivo role of...
The retinal G protein-coupled receptor (RGR) is a visual cycle photoisomerase that photopically regenerates 11-cis-retinal (11cRAL). It plays a crucial role in sustaining vision. Here, we investigated the in vivo role of RGR in the cone photoreceptor-dominant, zebrafish retina, focusing predominantly on how visual function is impacted in the absence of RGR. There are two zebrafish RGR paralogs, rgra and rgrb, both with predominant expression in retinal pigment epithelium (RPE) and Müller glia cells. Under standard light rearing conditions, bespoke rgrb; rgra double knockout zebrafish present with a ~21% reduction in optokinetic response (OKR) saccades per minute relative to wild-type (WT). This impaired visual behavior worsens in higher photopic conditions ranging from 20 000-81 000 lx. In contrast, no significant OKR defect is observed under dark-adapted conditions, consolidating the light-dependent role of RGR in vision. Retinoid profiling of rgrb; rgra zebrafish larvae demonstrated significant decreases in 11cRAL levels under standard and brighter light rearing conditions. Proteomic profiling validated the successful generation of rgrb; rgra zebrafish and revealed an unanticipated upregulation in ocular extracellular matrix proteins. From polarized light microscopy, increased collagen fiber abundance with dysregulated organization in Bruch's membrane at the interface between the retina and choroid was observed. These novel findings demonstrate the role of RGR in sustaining visual function under cone-mediated photopic conditions, a concomitant deficit in the photopic visual cycle and a novel role in maintaining the integrity of Bruch's membrane.
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