关键词： Paravertebral muscle degeneration   EGR1-ATF3 signaling   Inflammaging   Cell death   RNA sequencing  

摘要： The paravertebral muscles play a critical role in maintaining dynamic spinal stability and physiological function. With aging, these muscles undergo senescence and degeneration, contributing to spinal instability and the development of low back pain. Age-related cellular death further accelerates chronic, low-grade inflammation termed "inflammaging and disrupts the extracellular matrix (ECM), representing a key pathogenic mechanism driving paravertebral muscle degeneration (PMD). However, the core regulatory genes orchestrating inflammaging in this context have yet to be fully elucidated. The paravertebral muscles play an important role in supporting dynamic stability and physiological function of the spine. This study identified 409 differentially expressed genes (DEGs) through RNA sequencing. Subsequent bioinformatics analysis revealed 81 functionally relevant DEGs, with several hub genes such as Activating Transcription Factor 3 (ATF3), Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A/p21), and Interleukin-6 (IL-6) being significantly upregulated. These genes are associated with cellular death, ECM metabolic dysregulation, and inflammaging. Functional experiments demonstrated that silencing ATF3 attenuated cellular death, reduced inflammatory signaling, and preserved ECM integrity by modulating downstream effectors including CDKN1A/p21, IL6, Gasdermin E (GSDME), and Glutathione Peroxidase 4 (GPX4). Further network analysis identified the Early Growth Response 1 (EGR1)-ATF3 signaling axis, with EGR1 knockdown protecting against PMD through downregulation of ATF3. These genes may also exhibit high specificity and sensitivity for distinguishing PMD, suggesting their potential utility as diagnostic biomarkers. Overall, this study provides new insights into the molecular mechanisms underlying PMD and offers promising targets for therapeutic intervention.

关键词： HOX   PBX   DUSP1   ATF3   HXR9   ageing  

摘要： Background/Objectives: The HOX genes encode a family of homeodomain-containing transcription factors that have important roles in defining cell and tissue identity in embryonic development, but which also show deregulated expression in many cancers and have been shown to have pro-oncogenic roles. Due to their functionally redundant nature, strategies to target HOX protein function in cancer have focused on their interaction with their PBX cofactor using competitive peptides such as HXR9. HOX/PBX inhibition triggers apoptosis through a sudden increase in target gene expression, including Fos, DUSP1, and ATF3, which are otherwise repressed by HOX/PBX binding. Methods: We analyzed publicly available transcriptomic data in the R2 platform. Results: We show that a specific subgroup of HOX genes is negatively correlated with Fos, DUSP1, and ATF3 expression in prostate cancer, and that this subgroup also shows a strong positive corelation with pathways that support tumour growth, most notably DNA repair and aminoacyl tRNA biosynthesis, and a negative correlation with genes that promote cell adhesion and prevent motility. In addition, this set of HOX genes strongly correlates with patient age, reflecting a previously identified progressive loss of regulation of HOX expression in normal peripheral blood cells. Conclusions: Our findings indicate these HOX genes may have pro-oncogenic functions in prostate cancer.

关键词： Vitiligo   Melanocytes   Ferroptosis   SIRT7   GPX4  

摘要： Introduction Vitiligo is a hypopigmentation disorder characterized by epidermal melanocyte loss. Endogenous and exogenous oxidative stress causes the regulated cell death (RCD) of melanocytes in vitiligo. Recent studies have indicated that ferroptosis participates in vitiligo pathogenesis. Nevertheless, the underlying regulatory mechanisms remain elusive. Sirtuins (SIRT1-7) are nicotinamide adenine dinucleotide (NAD) ± dependent histone deacetylases, which are involved in a diverse array of cellular and physiological processes, including the inhibition of stress-induced ferroptosis. Objective To investigate the potential regulatory mechanisms of SIRT7 in ferroptosis of vitiligo melanocytes. Methods The protein levels of ferroptosis-related molecules were detected in perilesional skin from vitiligo patients and healthy donors. Genetic intervention targeting SIRT7 and biochemical assays were utilized to study the critical role and regulatory mechanisms of SIRT7 against oxidative stress-induced ferroptosis in melanocytes. The establishment of a vitiligo mouse model with melanocyte-specific Sirt7 knockout mice ( Sirt7 MCKO) was engaged to verify the role of SIRT7 in vitiligo. Results We found that anti-ferroptosis molecule expressions were significantly downregulated in melanocytes localized in vitiligo perilesional skin. Vitiligo melanocytes exhibited increased susceptibility to ferroptosis induced by oxidative stress compared to normal melanocytes . Furthermore, the expression and activity of SIRT7 were severely impaired in vitiligo melanocytes, as verified by publicly-available single-cell RNA sequencing (scRNA-seq) data. Mechanistically, SIRT7 promoted the expression of glutathione peroxidase 4 (GPX4) to protect melanocytes against ferroptosis via drosophila mothers against decapentaplegic protein 3 (SMAD3)-activating transcription factor 3 (ATF3) signaling pathway. What’s more important, the melanocyte-specific Sirt7 knockout could exacerbate the progression of vit

关键词： activated transcription factor 3   atherosclerosis   autophagy   terazosin   vascular smooth muscle cells senescence  

摘要： Vascular smooth muscle cell (VSMC) senescence is a pivotal driver of atherosclerosis (AS), but molecular links to ageing-related dysfunction are unclear. It is aimed to identify regulators of VSMC senescence and develop clinical interventions for ageing-related AS. Using single-cell RNA sequencing of human atherosclerotic carotid arteries and immunofluorescence validation, activating transcription factor 3 (ATF3) is identified as central to VSMC senescence. Mechanistic studies employ SMC-specific ATF3 knockout mice, CUT&Tag-seq, RNA/protein interaction assays, and m6A epitranscriptomic analyses. To bridge discovery to therapy, high-throughput virtual screening is performed for ATF3-targeting compounds and functionally validated hits. ATF3 deficiency in VSMCs accelerates ageing-induced AS by promoting senescence. Multi-omics showed ATF3 activates ATG7, triggering autophagy, while cytoplasmic ATG7 enhances ATF3 nuclear translocation, establishing a positive feedback loop. Ageing increases m6A methylation and decreases the stability of Atf3 mRNA. Terazosin (TZ) diminishes the interaction between YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and Atf3 mRNA, helping to preserve Atf3 mRNA stability. TZ is a promising therapeutic strategy for delaying VSMC senescence and preventing AS. ATF3 protects against VSMC senescence and AS by orchestrating autophagy via a novel ATF3-ATG7 amplification loop. Repurposing TZ to stabilize ATF3 offers a translatable approach to combat ageing-driven cardiovascular disease.

关键词： liver   regeneration   chromatin dynamics   enhancers   transcription factors   development   hepatocyte   ATF3   NRF2  

摘要： The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.

关键词： Intracerebral hemorrhage   Ferroptosis   Inflammation   BRD4   ATF3  

摘要： BackgroundIntracerebral hemorrhage (ICH), a subtype of hemorrhagic stroke, is associated with high morbidity and mortality. This study aimed to investigate the role and underlying mechanism of bromodomain and extraterminal domain protein 4 (BRD4) in neural injury following *** in vitro ICH model was established by treating SH-SY5Y cells with hemin. BRD4 and activating transcription factor 3 (ATF3) expression levels were altered using short hairpin RNA and pcDNA3.1 expression vectors. Cell viability and death were assessed using Cell Counting Kit-8 (CCK-8) and TdT-mediated dUTP nick-end labeling (TUNEL) assays. mRNA and protein expression levels were quantified by RT-qPCR and western blotting, respectively. Cytokine secretion was measured using enzyme-linked immunosorbent assay (ELISA) kits. Ferroptosis was evaluated based on levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and Fe2(+). Chromatin immunoprecipitation (ChIP) was performed to examine the interaction between BRD4, histone 3 lysine 27 acetylation (H3K27ac), and the ATF3 ***4 expression was upregulated in hemin-treated SH-SY5Y cells, and its knockdown repressed inflammation and ferroptosis induced by hemin. ATF3 expression was also elevated upon hemin stimulation and was identified as a downstream target of BRD4. Mechanistic studies revealed that BRD4 cooperated with H3K27ac to bind the ATF3 promoter, thereby promoting ATF3 transcription. Functional rescue experiments further demonstrated that ATF3 overexpression counteracted the inhibitory effects of BRD4 knockdown on hemin-induced inflammation and ***4 silencing alleviated hemin-induced neuronal ferroptosis and inflammation by regulating ATF3 transcription, suggesting that BRD4 inhibition may represent a potential therapeutic strategy for ICH.

关键词： Toxoplasma gondii   Adverse pregnancy outcomes   Macrophages   Trem2 promoter   ATF3  

摘要： BackgroundApproximately one in three people worldwide have been exposed to Toxoplasma gondii (T. gondii). Primary infection with T. gondii during pregnancy can cause severe complications. Our previous study demonstrated that deficiency of triggering receptor expressed on myeloid cells 2 (Trem2) exacerbates pregnancy-related complications in T. gondii-infected mice. However, understanding the mechanisms by which T. gondii modulates Trem2 expression in macrophages remains an unmet *** mouse pregnancy model of T. gondii infection and an in vitro cellular stimulation model using soluble T. gondii antigens (sTgAg) were used to assess Trem2 expression. Recombinant plasmids containing the full-length Trem2 promoter were constructed to evaluate the effect of sTgAg on promoter activity, followed by the construction of truncated promoter plasmids to identify key regulatory regions. Transcription factors potentially binding to the Trem2 promoter were predicted using PROMO and JASPAR, with ATF3 identified as responsive to sTgAg stimulation via western blot analysis. The binding of ATF3 to the Trem2 promoter was validated by chromatin immunoprecipitation (ChIP) assays. Finally, ATF3 knockdown experiments were performed to determine its role in mediating the inhibitory effect of sTgAg on Trem2 ***. gondii significantly suppressed Trem2 expression in both mouse placentas and cellular models, with truncated promoter assays identifying key regulatory regions of the Trem2 promoter inhibited by sTgAg. ATF3 was identified as a transcription factor responsive to sTgAg stimulation, which bound to the Trem2 promoter. Importantly, knockdown of ATF3 restored Trem2 expression, demonstrating its critical role in mediating the inhibitory effect of *** identified that sTgAg may target and inhibit Trem2 expression through the transcription factor ATF3, and inhibition of ATF3 activity may help maintain Trem2 expression in macrophages, providing a pot

关键词： Activating transcription factor 3   Sishen pill   Ulcerative colitis   Neutrophil extracellular traps   ERK/MMP9   CXCL1/CXCR2  

摘要： Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options, particularly for moderate-to-severe cases. The present study evaluated the therapeutic potential of Sishen Pill (SSP) through Activating Transcription Factor 3 (ATF3). Methods: Colonic biopsy samples were collected from 11 UC patients and 6 healthy controls (HCs). A murine colitis model was established using dextran sodium sulfate (DSS) and treated with SSP. The therapeutic efficacy of SSP was evaluated by measuring body weight, colonic length, and inflammatory markers in wild-type (WT) mice. Transcriptomic analysis revealed differentially expressed genes in colonic tissues following Atf3 knockout. Western blotting, immunofluorescence, immunohistochemical, and Luminex assays were conducted to assess the effect of SSP on Neutrophil Extracellular Traps (NETs) formation and ATF3 signaling. Results: ATF3 expression was significantly reduced in the inflamed mucosa of UC patients, correlating with disease severity. UC tissues also exhibited increased spontaneous NETs formation. In DSS-induced colitis mice, ATF3 expression was similarly reduced, whereas SSP treatment upregulated ATF3, mitigated weight loss, reduced colonic shortening, alleviated histopathological damage, and lowered inflammatory cytokine levels. Atf3 knockout mice (Atf3-/-) displayed more severe DSS-induced colitis with enhanced immune response as compared to control littermates (Atf3+/+). Transcriptomic analyses revealed that SSP downregulated key genes involved in NETs formation pathways, tumor necrosis factor (TNF) and cytokine-cytokine receptor signaling. Experimental validation confirmed that SSP reduced the levels of NETs-related proteins [Myeloperoxidase (MPO), Peptidylarginine Deiminase 4 (PAD4), Lymphocyte Antigen 6 Complex, G (Ly6G), Neutrophil Elastase (NE), Citrullinated Histone H3 (CitH3)] in the colorectal tissue of colitis mice. It also down-regulated TNF pathway-related proteins [Ph

关键词： hidradenitis suppurativa   epigenetic regulation   single-nucleus chromatin accessibility   ATF3  

摘要： Background/Objectives: Hidradenitis suppurativa (HS) is a complicated chronic inflammatory skin disorder characterized by recurrent and painful deep-seated nodules, abscesses, fistulae, scarring, and sinus tracts. HS most commonly affects high-density hair follicles and apocrine gland-rich regions of the body, including the axillae, inguinal folds, breasts, and perianal areas. Although genetic predisposition and environmental factors are known to contribute to the development and the severity of HS, the molecular mechanisms of HS are largely unknown. Methods: In this study, we employed global epigenetic and genomic data analysis and single-nucleus ATAC-seq (snATAC-seq) to profile the heterogeneity of HS-associated chromatin accessibility and define the underlying disease drivers. We additionally performed high-resolution immunofluorescence staining to confirm a novel candidate regulator. Results: We found that multiple skin development modules and molecular signal pathways were epigenetically dysregulated in HS basal CD49fhigh cells. Importantly, our snATAC-seq revealed a previously unraveled role for a transcription factor, ATF3, in transcriptionally regulating HS-associated genes. We also delineated the specific ATF3 expression pattern across the HS lesional skin. Conclusions: We characterize HS-specific epigenetic plasticity and chromatin state at the single-nucleus level and further underscore a possible mechanism for HS pathogenesis.

关键词： apoptosis   dopamine D1 receptors   glucocorticoid-associated ONFH   osteogenesis  

摘要： The nervous system plays a pivotal regulatory role in the maintenance of bone homeostasis, and the protective effects of dopamine and its receptors on bone metabolism are emerging. Despite these protective roles, the functional contribution of dopaminergic signaling, particularly through specific receptor subtypes, remains unexplored in glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) pathogenesis. Here, the dopamine D1 receptor (DRD1), a G protein-coupled receptor with few identified bone-related functions, is identified as a positive regulator of GC-induced apoptosis. The dopamine levels in the serum of GC-associated ONFH patients are significantly lower than those in the normal population. The protein and gene expression levels of DRD1 and the number of DRD1-positive cells are abnormally elevated in the pathological state of GC-associated ONFH, and DRD1 is expressed in osteoblasts. Overexpression of DRD1 attenuates GC-induced osteogenic inhibition and apoptosis in vivo and in vitro. Mechanistically, overexpression of DRD1 elevates cAMP levels, activates downstream protein kinase A, and inhibits GC-induced endoplasmic reticulum stress and apoptosis through the ATF3/CHOP signaling pathway, thus improving bone homeostasis. Importantly, Madopar, an FDA-approved dopaminergic agent, inhibits GC-induced osteoblastic apoptosis and ONFH via DRD1. Collectively, this study not only deciphers a previously unrecognized DRD1-mediated neuro-osteogenic axis but also repurposes an FDA-approved drug (Madopar) for precision ONFH management.