cGAS-STING Signaling Pathway Research Articles

Decursin protects against DSS-induced experimental colitis in mice by inhibiting the cGAS-STING signaling pathway.

While studies have shown that Angelica gigas Nakai (A. gigas) can alleviate ulcerative colitis in mice, the therapeutic role of its main active ingredient, decursin, is uncertain. Therefore, we aimed to investigate the protective effect and mechanism of decursin against inflammatory bowel disease (IBD) in vivo using mice. IBD was simulated via induction with 3% dextran sodium sulfate (DSS), with or without daily treatment with decursin (10 mg/kg or 20 mg/kg) or 5-amino salicylic acid (5-ASA; 100 mg/kg) for 14 days. Mice were weighed and monitored daily for disease activity index (DAI) scoring. Colon tissues were collected for histopathological staining analysis, and serum was collected for ELISA measurement of proinflammatory cytokines. Western blotting was employed to analyze colonic expression levels of the tight junction-related proteins ZO-1, Occludin, and Claudin 1, as well as cGAS-STING signaling pathway-associated proteins. The expression levels of major proteins were verified using immunohistochemistry and immunofluorescence. Compared with the control group, DSS-induced mice showed decreased body weight, increased DAI scores, shortening of the colon, disrupted colon tissue structure, increased serum levels of proinflammatory cytokines, increased expression of factors involved in activating the cGAS-STING signaling pathway, and reduced expression of ZO-1, Occludin, and Claudin 1. Under decursin treatment, the pathological state of IBD was less severe, proinflammatory factors were downregulated, and activation of the cGAS-STING signaling pathway was inhibited. Our findings indicate that decursin helps restore the intestinal mucosal barrier and prevents activation of the cGAS-STING signaling cascade, alleviating experimental IBD in mice.

The cGAS-STING pathway in HIV-1 and Mycobacterium tuberculosis coinfection.

Mycobacterium tuberculosis (M. tuberculosis) infection is the most common opportunistic infection in human immunodeficiency virus-1 (HIV-1)-infected individuals, and the mutual reinforcement of these two pathogens may accelerate disease progression and lead to rapid mortality. Therefore, HIV-1/M. tuberculosis coinfection is one of the major global public health concerns. HIV-1 infection is the greatest risk factor for M. tuberculosis infection and increases the likelihood of endogenous relapse and exogenous reinfection with M. tuberculosis. Moreover, M. tuberculosis further increases HIV-1 replication and the occurrence of chronic immune activation, accelerating the progression of HIV-1 disease. Exploring the pathogenesis of HIV-1/M. tuberculosis coinfections is essential for the development of novel treatments to reduce the global burden of tuberculosis. Innate immunity, which is the first line of host immune defense, plays a critical role in resisting HIV-1 and M. tuberculosis infections. The role of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, which is a major DNA-sensing innate immune signaling pathway, in HIV-1 infection and M. tuberculosis infection has been intensively studied. This paper reviews the role of the cGAS-STING signaling pathway in HIV-1 infection and M. tuberculosis infection and discusses the possible role of this pathway in HIV-1/M. tuberculosis coinfection to provide new insight into the pathogenesis of HIV-1/M. tuberculosis coinfection and the development of novel therapeutic strategies.

How Does African Swine Fever Virus Evade the cGAS-STING Pathway?

African swine fever (ASF), a highly infectious and devastating disease affecting both domestic pigs and wild boars, is caused by the African swine fever virus (ASFV). ASF has resulted in rapid global spread of the disease, leading to significant economic losses within the swine industry. A significant obstacle to the creation of safe and effective ASF vaccines is the existing knowledge gap regarding the pathogenesis of ASFV and its mechanisms of immune evasion. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is a major pathway mediating type I interferon (IFN) antiviral immune response against infections by diverse classes of pathogens that contain DNA or generate DNA in their life cycles. To evade the host’s innate immune response, ASFV encodes many proteins that inhibit the production of type I IFN by antagonizing the cGAS-STING signaling pathway. Multiple proteins of ASFV are involved in promoting viral replication by protein–protein interaction during ASFV infection. The protein QP383R could impair the function of cGAS. The proteins EP364R, C129R and B175L could disturb the function of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The proteins E248R, L83L, MGF505-11R, MGF505-7R, H240R, CD2v, E184L, B175L and p17 could interfere with the function of STING. The proteins MGF360-11L, MGF505-7R, I215L, DP96R, A151R and S273R could affect the function of TANK Binding Kinase 1 (TBK1) and IκB kinase ε (IKKε). The proteins MGF360-14L, M1249L, E120R, S273R, D129L, E301R, DP96R, MGF505-7R and I226R could inhibit the function of Interferon Regulatory Factor 3 (IRF3). The proteins MGF360-12L, MGF505-7R/A528R, UBCv1 and A238L could inhibit the function of nuclear factor kappa B (NF-Κb).

Transcriptome-based characterization of 3’2’-cGAMP signaling mediated immune responses

Cyclic dinucleotides (CDNs) are critical adjuvants in antiviral vaccines and cancer immunotherapy, primarily through the activation of the cGAS-STING signaling pathway. Evaluating the immune responses triggered by CDNs is essential for the development of effective adjuvants. In this study, we performed a comparative transcriptome analysis to characterize the immune responses elicited by the recently identified nuclease-resistant Drosophila and bacterial CDN, 3’2’-cGAMP, in mammalian immune cells. We detected a robust induction of innate immune gene signature following 3’2’-cGAMP stimulation in digitonin-permeabilized mouse primary macrophages, comparable to the response observed with the canonical mammalian CDN, 2’3’-cGAMP. STING deficiency remarkably reduced 3’2’-cGAMP-induced phosphorylation of TBK1 and IRF3 and the induction of IFN-β, indicating that 3’2’-cGAMP signaling-mediated immune responses were mainly STING dependent. In comparison to 2’3’-cGAMP signaling, 3’2’-cGAMP signaling preferentially elicited many STING-dependent genes involved in transcription and nucleosome positioning and assembly in the nucleus, which are likely associated with several enriched pathways, including cellular senescence, HDACs deacetylate histones, and epigenetic regulation of gene expression. The integrative analysis further revealed that 3’2’-cGAMP signaling preferentially induced genes were associated with autoimmune disease-related processes, suggesting a potential side effect that requires monitoring when used as an adjuvant. In conclusion, this study provides the first transcriptional landscape of 3’2’-cGAMP signaling in mammals and reveals the immune response characteristics and potential side effects mediated by 3’2’-cGAMP signaling. These findings may aid in the development of 3’2’-cGAMP-based adjuvants for antiviral vaccines and cancer immunotherapy.

Bioengineering human heavy-chain nanoferritin for glioblastoma multiforme-specific delivery and efficient immunotherapy

The blood–brain barrier (BBB) caused limited drug accumulation and programmed death-ligand 1 (PD-L1) compromised immunosuppressive microenvironment are bottlenecks in glioblastoma multiforme (GBM) treatment. Herein, we bioengineered a human heavy chain nanoferritin (HTE NPs) for GBM-specific delivery and efficient immunotherapy. To achieve targeted mitochondrial metabolic regulation, we connected triphenylphosphonium (TPP) with the photosensitive agent IR780 to form T780, which self-assembles with esomeprazole magnesium (EM) and human H-ferritin (HFn) to obtain HTE NPs. HFn endows HTE NPs with BBB penetration and specific site-targeting capabilities, thereby enhancing tumor accumulation and pH-responsive release within GBM cells. T780 subsequently induces mitochondrial damage, activating the AMP-dependent protein kinase (AMPK) pathway and blocking the transmission of T-cell inhibitory signals through the phosphorylation of PD-L1, thereby promoting T-cell activation. Moreover, EM inhibits the release of extracellular vesicles (EVs), reducing the inhibitory effect of PD-L1 on circulating T cells. Furthermore, mitochondrial impairment-induced mitochondrial DNA (mtDNA) leakage activates the cGAS-STING signaling pathway, inducing the maturation of dendritic cells (DCs), recruiting supportive immune cells to clear GBM cells, and improving the immunosuppressive microenvironment. Therefore, HTE NPs not only achieve efficient tumor accumulation but also facilitate the activation immune response, providing a promising strategy for the clinical treatment of GBM.

The role of the cGAS-STING pathway in chronic pulmonary inflammatory diseases.

The innate immune system plays a vital role in the inflammatory process, serving as a crucial mechanism for the body to respond to infection, cellular stress, and tissue damage. The cGAS-STING signaling pathway is pivotal in the onset and progression of various autoimmune diseases and chronic inflammation. By recognizing cytoplasmic DNA, this pathway initiates and regulates inflammation and antiviral responses within the innate immune system. Consequently, the regulation of the cGAS-STING pathway has become a prominent area of interest in the treatment of many diseases. Chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis, are characterized by persistent or recurrent lung inflammation and tissue damage, leading to diminished respiratory function. This paper explores the mechanism of action of the cGAS-STING signaling pathway in these diseases, examines the development of STING inhibitors and nanomaterial applications, and discusses the potential clinical application prospects of targeting the cGAS-STING pathway in chronic inflammatory lung diseases.

Dual-tDCS Ameliorates Cerebral Injury and Promotes Motor Function Recovery via cGAS-STING Signaling Pathway in a Rat Model of Ischemic Stroke.

Ischemic stroke is one of the leading causes of death and disability. Dual transcranial direct current stimulation (dual-tDCS) is a promising intervention to treat ischemic stroke, but its efficacy and underlying mechanism remain to be verified. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has recently emerged as a key mediator in cerebral injury. However, little is known about the effect of cGAS-STING on neuronal damage in ischemic stroke, and it remains to be studied whether the cGAS-STING pathway is involved in tDCS intervention for ischemic stroke. Therefore, we aimed to investigate whether dual-tDCS can alleviate ischemic brain injury in a rat model of ischemic stroke and if so, whether via cGAS-STING pathway. Middle cerebral artery occlusion (MCAO) was employed to induce a rat model of ischemic stroke. Male SD rats weighing 250-280g were randomly assigned to the Sham, MCAO, Dual-tDCS, Dual-tDCS + RU.521, and Dual-tDCS + 2'3'-cGAMP groups, with 10 rats in each group completing the experiment. Behavioral, morphological, MRI, and molecular biological methods were performed. We found that the cGAS-STING pathway was activated and expressed in neurons after MCAO. Dual-tDCS improved motor function and infarct volume, inhibited neuronal apoptosis, promoted the expression of neurotrophins (BDNF and NGF), CD31, and VEGF, and suppressed inflammation reaction after MCAO via the cGAS-STING pathway. Taken together, dual-tDCS may improve MCAO-induced brain injury and promote the recovery of motor function, resulting from the inhibition of neuronal apoptosis and inflammation reaction, as well as promotion of the expression of nerve plasticity- and angiogenesis-related proteins, via cGAS-STING pathway.

Recent advancements in cGAS-STING activation, tumor immune evasion, and therapeutic implications.

The cGAS-STING signaling pathway is indeed a pivotal component of the immune system and serve as a crucial link between innate and adaptive immune responses. STING is involved in the cellular response to pathogen invasion and DNA damage, and which has important consequences for host defense mechanisms and cancer regulation. Ongoing research aiming to modulate the cGAS-STING pathway for improved clinical outcomes in cancer and autoimmune diseases is underway. Indeed, the interaction between the cGAS-STING pathway and immune evasion mechanisms is a complex and critical aspect of cancer biology. Pathogens and various host factors can exploit this pathway to reduce the effectiveness of cancer therapies, particularly immunotherapies. Thus, immunotherapies or combination therapies may assist in overcoming the immune suppression and improving clinical outcomes. This review explores recent advancements in understanding the cGAS-STING signaling pathway, with particular emphasis on its activation mechanisms and role in tumor immune evasion. The dual role of the pathway in boosting immune responses while simultaneously enabling tumors to evade the immune system makes it a crucial target for innovative cancer treatment approaches.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 2 Given name: [Md Mazedul] Last name [Islam], Author 3 Given name: [Mst Rubaiat Nazneen] Last name [Akhand] and Author 5 Given name: [Md Rashedunnabi] Last name [Akanda]. Also, kindly confirm the details in the metadata are correct.AQ1: Here Author 4 given name: [Byung-Yong] Last name [Park] is missing. Metadata are correct.

Corilagin inhibits human cytomegalovirus infection and replication via activating the cGAS-STING signaling pathway in vitro and in vivo

AimThe existence of human cytomegalovirus (HCMV) is extremely widespread, causing serious diseases in patients with low immune function. The purpose of this study is to explore the efficacy and mechanism of Corilagin in the control of CMV infection, in order to provide scientific basis for the control of CMV infection. MethodsOur study employed an animal model in Balb/c mice, infected with MCMV, alongside cellular models in HFF cells and THP-1 cells, stimulated with HCMV. The expression of cGAS-STING signaling pathway molecules was detected in liver tissue, lung tissue, serum, cells and cell supernatant. The liver function and histopathological changes of mice were evaluated. ResultsIn vivo and in vitro experiments showed that Corilagin significantly inhibits CMV levels and attenuates pathological damage in liver and lung tissues in vivo, and similarly inhibits viral load in cells in vitro. Corilagin promotes the expression levels of STING and its downstream molecules in vivo and in vitro. Inhibition/down-regulation of STING significantly promotes CMV replication, on the contrary, activation/up-regulation of STING inhibits CMV replication, and Corilagin also promotes the expression levels of molecules related to the cGAS-STING signaling pathway in the above cases. ConclusionCorilagin could effectively inhibit the infection and replication of CMV in vitro and in vivo, which may be through the activation of cGAS-STING signaling pathway.

Bidirectional regulation of the cGAS-STING pathway in the immunosuppressive tumor microenvironment and its association with immunotherapy.

Adaptive anti-tumor immunity is currently dependent on the natural immune system of the body. The emergence of tumor immunotherapy has improved prognosis and prolonged the survival cycle of patients. Current mainstream immunotherapies, including immune checkpoint blockade, chimeric antigen receptor T-cell immunotherapy, and monoclonal antibody therapy, are linked to natural immunity. The cGAS-STING pathway is an important natural immunity signaling pathway that plays an important role in fighting against the invasion of foreign pathogens and maintaining the homeostasis of the organism. Increasing evidence suggests that the cGAS-STING pathway plays a key role in tumor immunity, and the combination of STING-related agonists can significantly enhance the efficacy of immunotherapy and reduce the emergence of immunotherapeutic resistance. However, the cGAS-STING pathway is a double-edged sword, and its activation can enhance anti-tumor immunity and immunosuppression. Immunosuppressive cells, including M2 macrophages, MDSC, and regulatory T cells, in the tumor microenvironment play a crucial role in tumor escape, thereby affecting the immunotherapy effect. The cGAS-STING signaling pathway can bi-directionally regulate this group of immunosuppressive cells, and targeting this pathway can affect the function of immunosuppressive cells, providing new ideas for immunotherapy. In this study, we summarize the activation pathway of the cGAS-STING pathway and its immunological function and elaborate on the key role of this pathway in immune escape mediated by the tumor immunosuppressive microenvironment. Finally, we summarize the mainstream immunotherapeutic approaches related to this pathway and explore ways to improve them, thereby providing guidelines for further clinical services.

Long-term transcranial ultrasound stimulation regulates neuroinflammation to ameliorate post–myocardial infarction cardiac arrhythmia and remodeling

BackgroundSympathetic overactivation and neuroinflammation in the paraventricular nucleus (PVN) are crucial factors in post–myocardial infarction (MI) cardiac remodeling and ventricular arrhythmias (VAs). Prior study has indicated that low-intensity focused ultrasound stimulation could attenuate sympathetic neuroinflammation within the PVN to prevent the occurrence of VAs in an acute MI model. Meanwhile, the cGAS-STING pathway has shown potential to ameliorate the neuroinflammatory response. However, the effect and mechanisms of long-term transcranial ultrasound stimulation (LTUS) for modulating neuroinflammation in the chronic stage of MI remain unclear. ObjectiveThis study aimed to ascertain whether LTUS could mitigate post-MI neuroinflammation and improve cardiac arrhythmia and remodeling through the cGAS-STING pathway. MethodsThirty-six SD rats were equally randomized to the sham group (pseudo-MI modeling), chronic MI group (MI modeling), and LTUS group (MI modeling and long-term ultrasound stimulation). Transcranial ultrasound stimulation (15 min/d) was conducted on the PVN for 4 consecutive weeks. After 4-week intervention, echocardiography, electrophysiologic experiments, and histopathologic staining were performed to assess the role of LTUS on post-MI neuroinflammation and cardiac remodeling. ResultsThe results indicated that LTUS significantly facilitated microglial M1 to M2 polarization through the cGAS-STING signaling pathway within the PVN. Furthermore, LTUS inhibited MI-induced sympathetic neuroinflammation, thereby improving cardiac dysfunction, ameliorating cardiac remodeling, and reducing VA inducibility. ConclusionLong-term ultrasound stimulation of the PVN was found to alleviate post-MI neuroinflammation and to improve cardiac remodeling, which might inspire novel insights and clinical strategies for noninvasive neuromodulation and the treatment of post-MI VAs.

Review of Excessive Cytosolic DNA and Its Role in AIM2 and cGAS-STING Mediated Psoriasis Development.

In psoriasis, keratinocytes are triggered by factors, such as infection or tissue damage, to release DNA, which thereby activates plasmacytoid dendritic cells and macrophages to induce inflammation, thickened epidermis, and parakeratosis. The recognition of double-stranded (ds)DNA facilitates the activation of cytoplasmic DNA sensors absent in melanoma 2 (AIM2) inflammasome assembly and cyclic guanosine monophosphate adenosine monophosphate (cGAMP) synthase (cGAS) - stimulator of interferon gene (STING) pathway, both of which play a pivotal role in mediating the inflammatory response and driving the progression of psoriasis. Additionally, secreted proinflammatory cytokines can stimulate further DNA release from keratinocytes. Notably, the activation of AIM2 and cGAS-STING signaling pathways also mediates programmed cell death, potentially enhancing DNA overproduction. As a result, excessive DNA can activate these pathways, amplifying persistent inflammatory responses that contribute to the maintenance of psoriasis. Several studies have validated that targeting DNA and its mediated activation of AIM2 and cGAS-STING offers promising therapeutic strategies for psoriasis. Here, we postulate a hypothesis that excessive cytosolic DNA can activate AIM2 and cGAS-STING, mediating inflammation and programmed cell death, ultimately fostering DNA accumulation and contributing to the development of psoriasis.

The role of cGAS-STING signaling in rheumatoid arthritis: from pathogenesis to therapeutic targets.

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily characterized by erosive and symmetric polyarthritis. As a pivotal axis in the regulation of type I interferon (IFN-I) and innate immunity, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has been implicated in the pathogenesis of RA. This pathway mainly functions by regulating cell survival, pyroptosis, migration, and invasion. Therefore, understanding the sources of cell-free DNA and the mechanisms underlying the activation and regulation of cGAS-STING signaling in RA offers a promising avenue for targeted therapies. Early detection and interventions targeting the cGAS-STING signaling are important for reducing the medical burden on individuals and healthcare systems. Herein, we review the existing literature pertaining to the role of cGAS-STING signaling in RA, and discuss current applications and future directions for targeting the cGAS-STING signaling in RA treatments.

Biodegradable oxygen-evolving metalloantibiotics for spatiotemporal sono-metalloimmunotherapy against orthopaedic biofilm infections

Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO2-hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H2O2-enriched biofilm microenvironment, MnPM can convert abundant H2O2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.

Prophylactic Effects of Betaine on Depression and Anxiety Behaviors in Mice with Dextran Sulfate Sodium-Induced Colitis.

Ulcerative colitis (UC) is a typical type of inflammatory bowl disease, which is accompanied by an increased risk of depression and anxiety-related psychological symptoms. Betaine is a naturally derived compound that can function as an anti-inflammatory drug and a neuromodulator. In-depth exploration of the potential role of betaine in treating UC-related depression and anxiety is crucial. This study aimed to elucidate the effects of betaine on UC-related depression and anxiety and clarify the underlying mechanisms. A dextran sulfate sodium (DSS)-induced mice model was established by 4% DSS drinking ad libitum for 7 days. The colonic injury was measured using hematoxylin-eosin (HE) staining and Alcian blue-periodic acid Schiff (AB-PAS) staining. Depression and anxiety-like behaviors were separately evaluated using a forced swimming test (FST), a tail suspension test (TST), a light-dark box test (LDBT), and an open field test (OFT). Immunohistochemistry was used to detect DNA damage and neurogenesis in the hippocampus. Western blotting was applied to detect the protein levels of macrophage polarization in mice colons and the alteration of mitochondrial dysfunction and the cGAS-STING pathway in the hippocampus. Betaine strongly alleviated mucosal structural disorder and mucin secretion reduction and promoted M2-macrophage polarization in the colon of DSS-treated mice. In addition, betaine could mitigate depression- and anxiety-like behaviors in DSS-treated mice, reduce the DNA damage and mitochondrial dysfunction, and inhibit the cGAS-STING signaling pathway. Our study reveals the antidepression/anxiety effects of betaine and further demonstrates the potential mechanism by which betaine inhibits DNA damage and mitochondrial dysfunction to block the cGAS-STING pathway, thereby repairing neurogenesis in the hippocampus.

Evaluating the therapeutic potential of genetically engineered probiotic Zbiotics (ZB183) for non-alcoholic steatohepatitis (NASH) management via modulation of the cGAS-STING pathway.

NAFLD/NASH has emerged as a global health concern with no FDA-approved treatment, necessitating the exploration of novel therapeutic elements for NASH. Probiotics are known as an important adjunct therapy in NASH. Zbiotics (ZB183) is the first commercially available genetically engineered probiotic. Herein, we aimed to evaluate the potential therapeutic effects of Zbiotics administration on NASH management by modulating the cGAS-STING-signaling pathway-related RNA network. In silico data analysis was performed and three DEGs (MAPK3/EDN1/TNF) were selected with their epigenetic modulators (miR-6888-5p miRNA, and lncRNA RABGAP1L-DT-206). The experimental design included NASH induction with an HSHF diet in Wistar rats and Zbiotics administration in NASH rats in comparison to statin treatment. Liver functions and lipid profile were assessed. Additionally, the expression levels of the constructed molecular network were assessed using RT-PCR. Moreover, the Zbiotics effects in NASH were further validated with histopathological examination of liver and colon samples. Also, immunohistochemistry staining of hepatic TNF-α and colonic occludin was assessed. Oral administration of Zbiotics for four weeks downregulated the expression of the cGAS-STING-related network (MAPK3/EDN1/TNF/miR-6888-5p miRNA/lncRNA RABGAP1L-DT-206) in NASH models. Zbiotics also ameliorated hepatic inflammation and steatosis, as evidenced by a notable improvement in NAS score and decreased hepatic TNF-α levels. Furthermore, Zbiotics exhibited favorable effects on colon health, including increased crypt length, reduced inflammatory cell infiltration, and restoration of colonic mucosa occludin expression. In conclusion, our findings suggest that Zbiotics has potential therapeutic effects on NASH via modulating the gut-liver axis and the cGAS-STING signaling pathway.

Arsenic-induced mtDNA release promotes inflammatory responses through cGAS-STING signaling in chicken hepatocytes

Arsenic is a toxic element that can cause severe liver damage in humans and animals. Arsenic-based inorganic pesticides, such as lead arsenate, copper arsenate, and calcium arsenate, are widely used for insect control and can eventually affect human health through accumulation in the food chain. However, the relationship between arsenic trioxide (ATO)-induced hepatotoxicity and the cGAS-STING signaling pathway has not been reported. The aim of this study was to investigate the potential role of inflammatory response in ATO-induced hepatotoxicity in chickens. In this study, we found that ATO exposure resulted in mtDNA leakage into the cytoplasm of chicken hepatocytes, which activated the cGAS-STING pathway and significantly increased the cGAS, STING, TBK1, and IRF7 mRNA and protein expression levels. Moreover, type I interferon response was activated. Concurrently, STING triggered the activation of the traditional NF-κB signaling pathway and promoted the expression of pro-inflammatory cytokine genes, including TNF-α, IL-6, and IL-1β. Subsequently, we found that both mtDNA clearance with EtBr and inhibition of the cGAS-STING pathway with H-151 reversed the ATO-induced innate immune and inflammatory responses. In summary, the above findings indicate that chicken hepatocytes can induce innate immune responses and inflammatory responses via mtDNA-cGAS-STING under ATO-exposure conditions, which is of great significance for further studies on the toxicity mechanism of ATO.

YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment

Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N6-methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.

The role of cGAS-STING signaling in the development and therapy of head and neck squamous cell carcinoma.

The cGAS-STING signaling pathway plays a critical role in innate immunity and defense against viral infections by orchestrating intracellular and adaptive immune responses to DNA. In the context of head and neck squamous cell carcinoma (HNSCC), this pathway has garnered significant attention due to its potential relevance in disease development and progression. HNSCC is strongly associated with risk factors such as smoking, heavy alcohol consumption, and human papillomavirus (HPV) infection. The presence or absence of HPV in HNSCC patients has been shown to have a profound impact on patient survival and prognosis, possibly due to the distinct biological characteristics of HPV-associated tumors. This review aims to provide a comprehensive overview of the current therapeutic approaches and challenges in HNSCC management, as well as the involvement of cGAS-STING signaling and its potential in the therapy of HNSCC. In addition, by advancing the present understanding of the mechanisms underlying this pathway, Activation of cGAS-STING-dependent inflammatory signaling downstream of chromosomal instability can exert both anti-tumoral and pro-tumoral effects in a cell-intrinsic manner, suggesting individualized therapy is of great importance. However, further exploration of the cGAS-STING signaling pathway is imperative for the effective management of HNSCC.

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.