The effect of inhibiting the cGAS-STING pathway in a chronic liver disease mouse model
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PROVIDER: PRJNA1160222 | ENA |
REPOSITORIES: ENA
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Project description:Hepatocellular carcinoma (HCC) mostly develops on the background of a chronic liver disease (CLD). The hallmarks of CLD includes increased hepatocyte apoptosis, compensatory proliferation and DNA damage. Mice with MCL-1 deficiency in hepatocytes (Mcl-1Dhep mice ) recapitulated these key features of CLD and developed HCC later in life. However, it is unclear how MCL-1 deficiency drives tumorigenesis. We analysed replication stress and the activation the cGAS-STING pathway in Mcl-1Dhep mice. 2-month-old Mcl-1Dhep mice showed increased replication stress, micronucleated hepatocytes and increased cytosolic DNA sensing. We found that an increase in extrachromosomal circular DNA in Mcl-1Dhep liver promoted a crosstalk between hepatocytes and immune cells to drive the immune response which was dependent on the canonical cGAS-STING pathway. We then generated Mcl-1Dhep/STING-/- double knockout mice to study the effects of inhibiting the cGAS-STING pathway in liver homeostasis and tumorigenesis. In fact, deletion of STING in Mcl-1Dhep mice reduced immune cell chemotaxis, as well as tumor incidence. Our findings indicate that the cytosolic DNA sensing pathway may play an important role in inflammation-driven liver carcinogenesis.
2025-09-09 | GSE277012 | GEO
Project description:The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using unbiased proteomic approaches, we report that Casein Kinase 1 alpha (CK1α) operates as a bimodal regulator of the cGAS-STING pathway. CK1α supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1α facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1α with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1α’s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development.
2026-09-10 | PXD063855 | Pride
Project description:The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using unbiased proteomic approaches, we report that Casein Kinase 1 alpha (CK1α) operates as a bimodal regulator of the cGAS-STING pathway. CK1α supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1α facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1α with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1α’s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development.
2026-09-14 | PXD066276 | Pride
Project description:The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using unbiased proteomic approaches, we report that Casein Kinase 1 alpha (CK1α) operates as a bimodal regulator of the cGAS-STING pathway. CK1α supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1α facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1α with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1α’s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development.
2026-09-14 | PXD066072 | Pride
Project description:The innate immune cGAS-STING pathway has emerged as an important signaling system in the organismal defense against viral and bacterial infections, inflammatory responses to cellular damage, regulation of autophagy, as well as in tumor immunosurveillance. Such key functions of the cGAS-STING pathway make it an attractive target for pharmacological intervention in disease treatments and in controlling inflammation and immunity. Here, we show that urolithin A (UA), an ellagic acid metabolite, exerts a profound effect on the expression of STING and enhances cGAS-STING activation and STING-related autophagy in response to cytosolic DNA in human cell lines. Animal laboratory models and limited human trials have reported no obvious adverse effects of UA administration. Thus, the use of UA alone or in combination with other pharmacological compounds may present a potential therapeutic approach in the treatment of human diseases that involves aberrant activation of the cGAS-STING pathway or accumulation of cytosolic DNA and warrants further investigation in relevant transgenic animal models.
2025-09-04 | GSE224258 | GEO
Project description:Background Chemical modifications on RNA profoundly impact RNA function and regulation. m6A, the most abundant RNA modification in eukaryotes, plays a pivotal role in diverse cellular processes and disease mechanisms. However, its importance is understudied in human chronic kidney disease (CKD) samples regarding its influence on pathological mechanisms. Methods LC-MS/MS and Methylated RNA Immunoprecipitation (MeRIP) sequencing were utilized to examine alterations in m6A levels and patterns in CKD samples. Overexpression of the m6A writer METTL3 in cultured kidney tubular cells was performed to confirm the impact of m6A in tubular cells and explore the biological functions of m6A modification on target genes. Additionally, tubule-specific deletion of Mettl3 (Ksp-Cre Mettl3f/f) mice and the use of anti-sense oligonucleotides inhibiting Mettl3 expression were utilized to reduce m6A modification in an animal kidney disease model. Results By examining 127 human CKD samples, we observed a significant increase in m6A modification and METTL3 expression in diseased kidneys. Epitranscriptomic analysis unveiled an enrichment of m6A modifications in transcripts associated with the activation of inflammatory signaling pathways, particularly the cGAS-STING pathway. m6A hypermethylation increased mRNA stability in cGAS and STING1, as well as elevated the expression of key proteins within the cGAS-STING pathway. Both the tubule-specific deletion of Mettl3 and the use of anti-sense oligonucleotides to inhibit Mettl3 expression protected mice from inflammation, reduced cytokine expression, decreased immune cell recruitment, and attenuated kidney fibrosis. Conclusions Our research revealed heightened METTL3-mediated m6A modification in fibrotic kidneys, particularly enriching the cGAS-STING pathway. This hypermethylation increased mRNA stability for cGAS and STING1, leading to sterile inflammation and fibrosis.
2024-07-03 | GSE271143 | GEO
Project description:Inflammation, as a crucial initial phase of bone healing, typically commences in the early stages of fracture repair. The cGAS-STING pathway serves as a key mediator of inflammation. The aim of this study is to explore the biological role and molecular mechanisms of the cGAS-STING pathway in the fracture healing process, with a particular focus on its function during the early inflammatory phase.
2025-09-19 | GSE308052 | GEO
Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact.
2022-08-18 | GSE211209 | GEO
Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact.
2022-08-18 | GSE211208 | GEO
Project description:We investigated the cGAS-STING inflammatory pathway differential activity among both sexes in T2DN rats and its impact on the temporal progression of the diabetic kidney disease. Here we used both male and female old and young T2DN rats. The cGAS-STING pathway presented distinct protein expression profiles between male and female T2DN rats, which significantly intensify with aging. In male T2DN rats, pro-inflammatory genes are particularly heightened in comparison to female rats of similar age, and such levels are further exacerbated with age. Interestingly, a comprehensive RNA-Seq analysis conducted in the kidney cortex of both sexes of T2DN rats, in younger and older ages, disclosed several central molecules, with crucial genes identified within the cGAS-STING pathway. Our study showed the intricate sexual differences in the development and progression of DKD and proposed the fundamental role of cGAS-STING pathway in disease development.
2023-09-13 | GSE243138 | GEO