关键词： Neuroprotection   Cerebral ischemic stroke   Ferroptosis   ATF3   Idebenone analog  

摘要： Ischemic stroke is a leading cause of morbidity and mortality worldwide. Despite its widespread impact, effective treatments remain limited. Idebenone (IDE) has shown promise in promoting recovery following stroke;however, its efficacy during the acute phase of ischemic stroke remains suboptimal. Therefore, the development of novel IDE analogs is of significant importance for improving outcomes in ischemic stroke treatment. Herein, we designed and synthesized a series of novel IDE analogs (1a-1g). An oxygen-glucose deprivation/reoxygenation (O/R) cell model and middle cerebral artery occlusion (MCAO) animal model were employed to investigate the effects of these drugs in vitro and in vivo, respectively. 1c was identified as the most promising candidate owing to its potent neuroprotective effects. Experimental analyses demonstrated that treatment with 1c reduced infarct size following ischemic injury and enhanced neuronal survival. 1c further alleviated neurodegeneration following ischemia/reperfusion (I/R) injury by inhibiting ferroptosis. Furthermore, our findings revealed that the expression of activating transcription factor 3 (ATF3) was upregulated after I/R injury, but markedly suppressed upon treatment with 1c. ATF3 overexpression downregulates the expression of SLC7A11 and GPX4, which are critical regulators of ferroptosis, thereby facilitating ferroptosis following I/R injury. Overall, our findings highlight the therapeutic potential of 1c in ischemic stroke and provide insight into the underlying mechanisms of its neuroprotective effects.

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

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： ATF3   Breast cancer   Oncogene   Tumor microenvironment   Tumor suppressor  

摘要： The adaptive response network uses activating transcription factor 3 (ATF3) as a central regulator, responding to stress signals. Basal levels of ATF3 expression maintain cellular homeostasis under normal physiological conditions. Various pathological conditions, including breast cancer, alter ATF3 expression through distinct regulatory mechanisms during disease progression. ATF3 acts as a tumor suppressor gene or an oncogene in a context-dependent manner. Particularly in breast cancer, ATF3 plays a multifaceted role by regulating cell proliferation, apoptosis, invasion, metastasis, and therapy resistance. The tumor microenvironment strongly influences ATF3 expression by modulating the immune landscape. Therefore, this review provides a brief overview of the influences on ATF3 expression and its interactions with key tumor-suppressive and oncogenic pathways in breast cancer. A more profound understanding of ATF3 and its role in breast cancer is crucial for the development of personalized therapeutic strategies to address the challenges posed by the heterogeneity of the disease. © 2025 Elsevier Inc.

关键词： Cellular stress response   Tumor   DNA damage response   Endoplasmic reticulum stress   Integrated stress response   Oxidative stress  

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.

摘要： Chronic wound healing, particularly in diabetic wounds, remains a global challenge. The delayed or even stagnant healing process imposes a substantial burden on both society and individuals. A critical challenge lies in effectively reducing inflammatory levels and promoting vascular remodeling. As an adipokine, C1QTNF9 (CTRP9) has been demonstrated to suppress inflammatory responses under various pathological conditions. In diabetic wound healing, CTRP9 facilitates the proliferation, differentiation, and migration of keratinocytes, yet its specific regulatory mechanisms on local inflammation remain unclear. Transcriptomic analysis of diabetic wounds revealed significantly reduced CTRP9 transcription levels in non-healing wounds. Animal experiments showed lower CTRP9 expression in the skin tissues of diabetic mice compared to normal mice, suggesting a close association between CTRP9 and wound healing. Subsequent local supplementation of CTRP9 in diabetic mouse wounds significantly accelerated healing to near-normal levels. Notably, SLC7A11 (also known as xCT)-a key protein linked to impaired efferocytosis in dendritic cells at diabetic wounds-was downregulated by CTRP9, while CTRP9 enhanced efferocytic efficiency. ATF3, a transcriptional repressor of SLC7A11 involved in ferroptosis regulation, has not been previously explored in dendritic cell efferocytosis. This study found that ATF3 knockdown upregulated SLC7A11 expression and attenuated CTRP9-mediated efferocytosis enhancement, indicating ATF3 as a critical pathway through which CTRP9 regulates SLC7A11. Furthermore, CTRP9 enhances glycolysis to produce lactate, thereby providing energy support for dendritic cell efferocytosis. In summary, this study demonstrates that CTRP9, as an anti-inflammatory factor, promotes diabetic wound healing by enhancing dendritic cell efferocytosis and reducing local inflammation, offering a promising therapeutic strategy.

关键词： Acute ischemic stroke   Apoptosis   ATF3   High-salt diet   Intermittent Theta-Burst Stimulation  

摘要： Acute ischemic stroke (AIS), a high-risk condition associated with significant morbidity and disability, could be further exacerbated by a high-salt diet (HSD). Although intermittent theta-burst stimulation (iTBS) is a clinically effective rehabilitation modality, its neuroprotective mechanisms remain unclear. This study aimed to elucidate the pathways through which HSD exacerbates early AIS injury, identify potential biomarkers, and assess the impact of iTBS intervention. First, bioinformatics techniques were employed to identify core genes associated with early ischemia and differentially expressed microglial genes (DEMGs) in mice subjected to middle cerebral artery occlusion (MCAO) with or without HSD. Subsequently, key pathways enriched among these DEMGs were elucidated. Next, co-expressed genes linked to HSD-exacerbated AIS mechanisms were selected as potential biomarkers and validated in vivo and in vitro. Finally, iTBS effects on biomarker expression were evaluated. As a result, integrative bioinformatics analysis implicated ATF3 as a potential biomarker for HSD-exacerbated AIS injury, mechanistically linked to HSD-induced microglial apoptosis. Consistently, HSD significantly upregulated ATF3 expression in both in vivo and in vitro AIS models. Furthermore, iTBS intervention significantly downregulated ATF3 expression within the HSD-exacerbated AIS context. Critically, iTBS also specifically downregulated ATF3 expression notably within hippocampal microglia of HSD-fed MCAO mice. Collectively, these findings suggest ATF3 serves as a potential biomarker for the combined injury induced by HSD and AIS and represents a promising therapeutic target for iTBS. © 2025 International Brain Research Organization (IBRO)

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 G4C2repeat 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-PR42 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： ATF3   Ferroptosis   PI3K/ Akt pathway   Sarcopenia  

摘要： PURPOSE:Sarcopenia, characterized by progressive skeletal muscle loss and weakness, has unclear pathogenesis and lacks targeted therapies. Emerging evidence implicates ferroptosis in sarcopenia progression, though its regulatory mechanisms remain undefined. This study investigates the ferroptosis-sarcopenia interplay, identifies core regulators and elucidates their molecular basis. METHODS:The experimental design combined in vivo and in vitro approaches using SAMP8 mice and C2C12 myoblast. Sarcopenia phenotypes were systematically characterized through functional assessments of mice, histomorphological analysis of gastrocnemius muscle, and quantification of iron deposition. Bioinformatics cross-analysis was performed by intersecting the sarcopenia-related gene expression dataset (GSE175495) with ferroptosis-associated genes from the FerrDb database, identifying ATF3 as a hub gene. Validation was conducted through Western blot (WB) and quantitative real-time PCR (qPCR). For mechanistic exploration, ferroptosis was induced in C2C12 cells using ferric ammonium citrate (FAC, 500 μM, 48 h), followed by lentivirus-mediated ATF3 overexpression. The regulatory role of ATF3 in ferroptosis was assessed via reactive oxygen species (ROS) assay, malondialdehyde (MDA) quantification, and FerroOrange fluorescent probe for intracellular iron detection. Transcriptome sequencing of ATF3-dysregulated cell lines was performed, and GO/ KEGG enrichment analyses were applied to identify critical signaling pathways. Functional validation was further conducted using pathway-specific inhibitors. RESULTS:Aged SAMP8 mice exhibited hallmark sarcopenia characteristics including 31 % reduction in grip strength, 42 % decrease in muscle fiber cross-sectional area, and 2.1-fold elevation in intramuscular iron content. Molecular analysis revealed age-dependent downregulation of ATF3 expression (57 % protein decrease, 63 % mRNA reduction). ATF3 overexpression in C2C12 cells significantly attenuated fe

关键词： Ferroptosis   GPX4   Melanocytes   SIRT7   Vitiligo  

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 vitilig

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.