摘要： During cellular stress, which results in DNA damage, protein, glucose, and lipid metabolism disorders, and redox homeostasis imbalance, various cellular stress responses are triggered, such as DNA damage response, endoplasmic reticulum stress, integrated stress response, and oxidative stress. These cellular stress responses play an important role in the disease process and have a dual role. Activating transcription factor3 belongs to the ATF/CREB family and is activated by stress. It is a transcription factor that plays an important role in gene regulation. It mainly participates in the regulation of disease progression by regulating metabolic homeostasis. Its expression is related to the prognosis of various tumors. ATF3, which is elevated in tumor cells by stress stimulation, not only participates in the repair of internal environment homeostasis mediated by cellular stress response, but also plays a key role in programmed cell death mediated by cellular stress response. Cellular stress response can affect the occurrence of ferroptosis through multiple pathways, with ATF3 being a key protein. This review first introduces the mechanism of ATF3 expression regulation, then summarizes the dual role of ATF3 in DNA damage response, endoplasmic reticulum stress, integrated stress response, and oxidative stress. Finally, it emphasizes the mechanism of ATF3 affecting ferroptosis through DNA damage response, and ER and oxidative stress. This study comprehensively reviews the role of ATF3 in tumors from multiple perspectives, providing new directions for tumor treatment.

关键词： Poly-PR   C9orf72   ALS   Pom121   Sigma-1R   Nucleocytoplasmic transport   Nuclear envelope integrity   Atf3  

摘要： Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72 -associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR 42 mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72 -linked ALS.

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： Albiflorin   Acetaminophen-induced liver injury   ATF3   Blood-biliary barrier  

摘要： Background: Acetaminophen-induced hepatotoxicity remains a clinical challenge with limited targeted therapeutic options. While recent advances have identified blood-biliary barrier disruption as a critical pathogenic mechanism, effective interventions preserving this barrier are notably lacking. Albiflorin, a key bioactive constituent of Paeonia lactiflora Pall., exhibits unique bile acid modulation along with antioxidant and antiinflammatory activities, suggesting its potential efficacy in preventing acetaminophen-induced liver injury. However, its specific role and underlying mechanisms in alleviating acetaminophen-induced hepatotoxicity remain unclear. Objective: This study's objective was to examine the pharmacological effects and primary molecular mechanisms of albiflorin in alleviating acetaminophen-induced liver injury. Methods: An acetaminophen-induced liver injury mouse model was created using a 300 mg/kg dose of acetaminophen. The hepatoprotective effects of albiflorin were assessed through histological and biochemical analyses. Blood-biliary barrier integrity was evaluated via Evans blue dye tests, immunofluorescence, and bile acid assays. Transcriptomic analysis, gene overexpression and interference techniques, and ChIP-qPCR were employed to explore the molecular mechanisms underlying the protective effects of albiflorin. Results: Albiflorin significantly reduced acetaminophen-induced liver injury, as evidenced by improved biochemical profiles and hepatocyte morphology. It also prevented increases in blood-biliary barrier permeability and bile acid levels. RNA sequencing identified 3,184 differentially expressed genes, revealing critical pathways involved in maintaining blood-biliary barrier integrity. AF reversed the acetaminophen-induced changes in the expression of genes related to the blood-biliary barrier, particularly occludin, claudin 5, ABCG5, and ABCG8. Albiflorin protected the blood-biliary barrier and mitigated acetaminophen-induced liver inju

关键词： ATF3   Axon regeneration   Bioenergetics   DRG neurons   Estrogen receptor   Mitochondria   PGC-1 alpha  

摘要： Adult rat dorsal root ganglion (DRG) sensory neurons express estrogen receptors (ERs) alpha and beta. Estrogen regulates multiple aspects of the nervous system including development, survival, and axonal outgrowth of DRG neurons. While previous studies have established estrogen's neuroprotective role in these neurons, the specific ER subtypes and downstream signaling pathways mediating these effects remain poorly defined. The objective of our study was to investigate the effects of 17 beta-estradiol (E2) on mitochondrial function and axonal regeneration of cultured DRG neurons and explore the pathways by which E2 acts. We observed that E2 treatment upregulated the levels of phosphorylated AMP-activated protein kinase (AMPK). E2 also increased the levels of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) and activating transcription factor 3 (ATF3), which are proteins involved in mitochondrial biogenesis and axonal regeneration. The Seahorse assay showed that E2 elevated basal respiration in cultured DRG neurons. Additionally, E2 treatment for 24 h significantly increased total neurite outgrowth of DRG neurons. Pharmacological inhibition of AMPK using Compound C inhibited E2-mediated increases in ATF3 expression and neurite outgrowth. The Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKK beta) inhibitor STO-609 blocked E2-mediated AMPK activation. Furthermore, we assessed whether these effects were mediated by ER alpha or ER beta by using the ER alpha selective agonist propyl pyrazole triol (PPT) and ER beta selective agonist diarylpropionitrile (DPN). PPT upregulated phosphorylated AMPK levels and increased total neurite outgrowth, whereas DPN was ineffective. The results demonstrate that E2 acts through ER alpha to promote neurite outgrowth via a pathway involving activation of CaMKK beta/AMPK in adult DRG neurons. Our findings identify ER alpha-mediated AMPK activation as a therapeutic target for enhancing neuronal rege

关键词： Wound healing   ATF3   Retin-A   Antimicrobial peptides  

摘要： Background: Wound healing is a complex and regulated process that involves the coordinated action of key signaling pathways. Activating transcription factor 3 (ATF3) is a stress-inducible protein that has recently emerged as a critical modulator of cellular responses to injury, including those involved in wound healing. Aim: The aim of this study was to explore the repurposing of existing pharmacological agents to activate ATF3 and evaluate their potential to enhance wound healing factors. Methods: We selected three compounds: retin-A, furosemide, and acrivastine based on their ability to modulate ATF3 expression and assessed their effects on wound healing processes in primary cell cultures. We evaluated wound healing-related genes such as LL-37, HBD-2, HBD-3, and VEGFA by qPCR, and a wound healing scratch assay using keratinocytes was conducted to evaluate cell migration. Results: Interestingly, retin-A induced the expression of key wound healing-related genes, including HBD-2, HBD-3, LL-37, and VEGF. Also, retin-A was the only compound showing wound healing effects, while furosemide and acrivastine did not exhibit any noticeable activity. Conclusion: Our research highlights the potential of retin-A as therapeutic agents to improve wound healing, particularly in chronic wound models.

关键词： Metformin   ferroptosis   skin cutaneous melanoma   ATF3   RNA-seq  

摘要： Background: To explore the effects of metformin on the proliferation and ferroptosis of skin cutaneous melanoma (SKCM) and its potential molecular mechanisms, providing a new theoretical basis and strategy for the treatment of cutaneous melanoma. Methods: The CCK-8 experiment was used to detect the effect of metformin on the proliferation of skin cutaneous melanoma cells. Kits were used to detect glutathione (GSH) content, reactive oxygen species (ROS), lipid peroxide (LPO), and malondialdehyde (MDA) levels to evaluate ferroptosis-related indicators. RNA-seq sequencing and related analyses were used to screen differentially expressed genes and explore their involved biological functions and signaling pathways. Western blot was used to detect the expression levels of ATF3 and NRF2 proteins and analyze the regulatory effect of metformin on the ATF3/NRF2 axis. Results: Metformin significantly reduced the proliferation ability of skin cutaneous melanoma cells. The treated cells showed a decrease in GSH content and an accumulation of ROS, LPO, and MDA, suggesting that ferroptosis was regulated. RNA-seq analysis found 2068 differentially expressed genes, of which 897 were up-regulated and 1171 were down-regulated. The related pathways such as iron metabolism disorders and ferroptosis were activated. After metformin treatment, the expression of ATF3 mRNA in cells increased and was positively correlated with the concentration, while the expression in SKCM tissues decreased. At the same time, the expression of ATF3 protein increased and the expression of NRF2 protein decreased, suggesting that metformin may induce ferroptosis through the ATF3/NRF2 axis. Conclusion: Metformin can induce ferroptosis by regulating ATF3/NRF2 axis, which may be a novel strategy for improving the treatment of skin cutaneous melanoma.

关键词： ATF4/ATF3/CHOP axis   Bioenergetics metabolism   DMC   Fe-S cluster   HCC therapeutics   Oxidative stress  

摘要： Demethoxycurcumin (DMC) has demonstrated remarkable anti-cancer properties across various tumor types. However, its efficacy in hepatocellular carcinoma (HCC) has not yet been established. Interestingly, the type of cell death induced by DMC was distinct from traditional pathways such as apoptosis, ferroptosis, necroptosis, pyroptosis, cuproptosis, and autophagy, indicating a need for further detailed exploration of its mechanisms. Our investigations revealed that DMC treatment led to a marked increase in oxidative stress, as evidenced by the accumulation of reactive oxygen species (ROS). This increase in ROS disrupted the iron-sulfur (Fe-S) cluster, impairing mitochondrial respiration. Additionally, ROS activation markedly reduced the rate of aerobic glycolysis by interfering with key glycolytic enzymes. The resultant inhibition of these bioenergetic pathways led to a significant depletion of ATP. Moreover, DMC activated the ATF4/ATF3/CHOP signaling axis, and the reduction of CHOP levels mitigated the cytotoxic effects of DMC in HCC cells. In conclusion, DMC initiated oxidative stress, which disrupted bioenergetic metabolism and activated the ATF4/ATF3/CHOP signaling pathway, ultimately leading to cell death in HCC cells. These findings suggest that DMC might have a potential role in the treatment of HCC. However, further validation through in vivo models and clinical trials is required to confirm the therapeutic potential of DMC against HCC. Moreover, more work is still needed to further explore the specific form of cell death induced by DMC.

关键词： Intervertebral disc degeneration   BATF2   ATF3   Mitochondrial dysfunction   Mitochondrial redox homeostasis  

摘要： Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, spinal instability, disc herniation and spinal stenosis, which is a serious risk to human health, yet its molecular mechanisms remain unknown. The basic leucine zipper ATF-like transcription factor 2 (BATF2) has been reported to play important roles in regulating cell proliferation, apoptosis, and inflammatory responses;however, its specific role in IVDD remains unknown. We firstly demonstrated BATF2 expression was significantly upregulated in degenerated nucleus pulposus (NP) tissues. Functional assays demonstrated that BATF2 overexpression promoted nucleus pulposus cell (NPC) apoptosis and extracellular matrix (ECM) catabolism in vitro and vivo. It is further demonstrated that BATF2 impairs mitochondrial function by disturbing mitochondrial redox homeostasis. Mechanistically, BATF2 stabilizes the activating transcription factor 3 (ATF3) by inhibiting the ubiquitination modification of ATF3. Notably, ATF3 overexpression accelerated NPC apoptosis and ECM degradation. More importantly, ATF3 knockdown reversed the effects of BATF2-induced mitochondrial dysfunction and IVDD progression. These results suggest that BATF2-ATF3 axis disrupts mitochondrial redox homeostasis to impair mitochondrial function, thereby exacerbating the progression of IVDD. Targeting BATF2-ATF3 axis could provide a potential strategy for IVDD treatment.

关键词： ATF3   Ischemic stroke   Genetic susceptibility   Single-nucleotide polymorphisms  

摘要： BackgroundGenetic factors play an important role in ischemic stroke (IS) onset. Activating transcription factor 3 (ATF3) is a known IS biomarker;however, the association between ATF3 polymorphisms and susceptibility to IS remains unclear. Therefore, we aimed to explore the association between ATF3 single-nucleotide polymorphisms (SNPs) and genetic susceptibility to IS in a population in Dali, Yunnan, *** included 145 patients with IS and 127 healthy controls in this case-control study. ATF3 SNP sites (rs1105899, rs1008737, rs1195474, and rs1195472) were genotyped using SNaPshot *** serum glucose (VSG), white blood cell count, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and systolic blood pressure (SBP) were IS risk factors;VSG had the highest impact on IS susceptibility, whereas SBP had the lowest. Genotype distributions of rs1105899, rs1008737, and rs1195472 polymorphisms in the control group conformed to the Hardy-Weinberg equilibrium. Association analysis between ATF3 polymorphisms and IS risk showed that rs1105899, rs1008737, and rs1195474 ATF3 polymorphisms were not significantly associated with IS risk. In the codominant and superdominant model of the rs1195472 [C/T] loci, CT genotype can reduce the risk of stroke, compared with TT and CC genotypes. Haplotype AGAC was an inhibitory factor for IS. The GTEx database showed that the rs1195472 CT genotype increased ATF3 expression and was associated with its expression in individual *** rs1195472 polymorphism was associated with IS risk in our study population;no significant correlation was noted between rs1105899, rs1008737, and rs1195474 polymorphisms and IS.