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.

关键词： ATF3   Breast cancer   Tumor microenvironment   Tumor suppressor   Oncogene  

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 contextdependent 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.

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： CD8+ t cells   IL-24   Immunotherapy   Melanoma   Vinburnine  

摘要： BACKGROUND:Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses. METHODS:This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases. RESULTS:This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8 T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches. CONCLUSIONS:These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immun

关键词： Acute ischemic stroke   High-salt diet   ATF3   Apoptosis   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.

关键词： LNP   iMDK   ATF3   CHOP   KRAS   lung cancer  

摘要： The small molecule iMDK induces apoptosis in H441 papillary lung adenocarcinoma cells that harbor KRASG12V;however, the molecular mechanism by which iMDK induces apoptosis remains unknown. In addition, due to its hydrophobic structure, iMDK is insoluble in water, making iMDK unsuitable for clinical translation. To understand the molecular mechanism, we conducted RNA-seq analysis to identify genes that are regulated by iMDK in H441 cells. RNA-seq data analysis indicated that iMDK activated the ATF3-CHOP (DDIT3)-mediated apoptotic pathway. iMDK did not induce apoptosis in ATF3 or CHOP CRISPR knockout H441 cells, indicating that iMDK induced apoptosis through the ATF3-CHOP pathway. Notably, iMDK also activated ATF3 and induced apoptosis in both sotorasib (KRASG12C inhibitor)-naive and resistant H358 bronchioalveolar carcinoma cells that harbor KRASG12C. To administer iMDK in water, we encapsulated iMDK in multiple lipid or polymer nanoparticles that could be suspended in water. Importantly, iMDK that was encapsulated in DPPC/DOTAP/DSPE-PEG/Cholesterol lipid nanoparticles but not DPPC/DPPG/DSPE-PEG/Cholesterol or PEI-PEG-LinA nanoparticles induced apoptosis in H441 cells in vitro. Intraperitoneal injection of water-soluble iMDK lipid nanoparticles (DPPC/DOTAP/DSPE-PEG/Cholesterol) significantly reduced the growth of H441 xenografts without inducing liver toxicity in vivo. These results suggest that water-soluble iMDK lipid nanoparticle delivery is effective for treating subtypes of KRAS mutant lung cancers that retain the ATF3-mediated apoptotic pathway.

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： Macrophages   Immunometabolism   Bone healing   Bone regeneration   Microenvironment   Metabolic reprogramming   OXPHOS   Oxidative phosphorylation   FAS   Fatty acid synthesis   FAO   Fatty acid oxidation   TCA cycle   Tricarboxylic acid cycle   MSCs   Mesenchymal stem cells   HIF-1α   Hypoxia-inducible factor-1 alpha   RANKL   Receptor activator of nuclear factor kappa-Β ligand   ROS   Reactive oxygen species   NO   Nitric oxide   LDH   Lactate dehydrogenase   PKM2   Pyruvate kinase M2   GLUT1   Glucose transporter 1   PFKFB3   6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3   PGC-1α   Peroxisome proliferator-activated receptor gamma coactivator 1-alpha   GIT1   G protein-coupled receptor kinase interacting protein 1   MSR1   Macrophage scavenger receptor 1   ETC   Electron transport chain   OCR   Oxygen consumption rate   ECAR   Extracellular acidification rate   MFN2   Mitofusin 2   OPA1   Optic atrophy 1   Drp1   Dynamin related protein 1   BMSCs   Bone marrow stromal cells   SDHB   Succinate dehydrogenase subunit B   PPAR   Peroxisome proliferator-activated receptor gamma   FOXO1   Forkhead box protein O1   CIC   Citrate carrier   ACLY   ATP-citrate lyase   PFK   Phosphofructokinase   Arg-1   Arginase-1   iNOS   Inducible nitric oxide synthase   α-KG   α-ketoglutarate   PDH   Pyruvate dehydrogenase   PHDs   Prolyl hydroxylases   GDH   Glutamate dehydrogenase   GLS   Glutaminase   ACOD1   Aconitate decarboxylase 1   ATF3   Activating transcription factor 3   TET2   Tet methylcytosine dioxygenase 2   IAA   Indole-3-acetic acid   IPA   Indole-3-propionic acid   M2-EVs   M2-derived extracellular vesicles   SUCNR1   Succinate receptor 1   NLRP3   NOD-like receptor protein 3   Nrf2   Nuclear factor erythroid 2-related factor 2   SCFAs   Short-chain fatty acids   LPS   Lipopolysaccharide   Trp   Tryptophan   AhR   Aryl hydrocarbon receptor   MLT   Melatonin   ADSCs   Adipose-derived mesenchymal stem cells   EVs   Extracellular vesicles  

摘要： Background Immunometabolism, the regulation of immune cell function through metabolic pathways, has emerged as a key focus in regenerative medicine. Traditional bone healing therapies primarily target the osteoblast–osteoclast regulatory axis, overlooking the metabolic reprogramming of immune cells (e.g., macrophages) and limiting regenerative efficiency. Macrophages orchestrate bone healing through dynamic shifts between proinflammatory (M1-like) and reparative (M2-like) metabolic phenotypes. Recent studies have shown that their immunometabolic transitions govern the sequential phases of bone healing. Therefore, targeting macrophage immunometabolism may offer a novel therapeutic paradigm for bone regeneration. Aim of review This review summarizes recent advances in understanding how macrophage metabolism regulates bone healing, emphasizing the critical role of immunometabolism in resolving inflammation and regenerating tissue throughout the repair process. By integrating insights from the fields of cellular metabolism, microenvironmental signals, and biomaterial science, this review aims to offer an integrative perspective on how targeting macrophage metabolic control could serve as a therapeutic strategy to enhance bone regeneration. Key scientific concepts of review This review addresses five core concepts. First, it delineates the spatiotemporal roles and phenotypic shifts of macrophages in the different phases of bone healing. Second, it explores how the reprogrammed metabolism of glucose, lipids, and amino acids underlies macrophage polarization and function. Third, it emphasizes how microenvironmental cues, including cytokines, metabolic intermediates, and microbiota-derived metabolites, modulate macrophage immunometabolism. Fourth, it summarizes emerging therapeutic strategies designed to regulate macrophage metabolism for bone regeneration, such as cell-based therapies, immunomodulatory hydrogels, and nanotechnologies. Finally, it identifies major challenge

摘要： Osteosarcoma stem cells (OSCs) are characterized by their self-renewal and multilineage differentiation abilities, contributing to osteosarcoma malignancy. The Warburg effect describes cancer cells' preference for glycolysis over mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Unlike differentiated cancer cells, cancer stem cells exhibit unique and diverse metabolic properties depending on the context. This study investigated the metabolic reliance of OSCs and related genes through in silico analyses of clinical osteosarcoma specimens and in vitro and in vivo genetic and pharmacological analyses. Glycolysis and OXPHOS pathways were more active in OSCs than in non-OSCs at single-cell resolution. Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme balancing glycolysis and OXPHOS, was upregulated in OSCs and correlated with poor prognosis in patients with osteosarcoma. Genetic inhibition of PDK1 via RNA interference reduced OSC stemness, glycolysis, and heterotopic tumor formation. Pharmacological inhibition of PDK1 mirrored these genetic effects and repressed orthotopic tumor burden and pulmonary metastasis. Activating transcription factor 3 (ATF3) was identified through screening as a downstream factor of PDK1-regulated OSC properties. ATF3 overexpression reversed the stemness reduction caused by PDK1 deficiency through, at least in part, activating the TGF-beta/Smad pathway without affecting the metabolic balance. ATF3 expression, glycolysis, and stemness were significantly induced by wild-type PDK1 overexpression but not by a kinase-dead PDK1 mutant in OSCs. Pharmacological inhibition of glycolysis counteracted the upregulation of ATF3 expression and increased stemness in OSCs by PDK1 overexpression. These findings indicate that PDK1 fine-tunes metabolic balance to govern OSC stemness and tumorigenicity through, at least in part, modulating ATF3/TGF-beta/Smad pathway, suggesting a potential therapeutic approach for targeting OSCs in osteosa