cGAS-STING Signaling Research Articles

HER2 regulates autophagy and promotes migration in gastric cancer cells through the cGAS-STING pathway.

In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06-3.54; P = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.

MVK, induced by Kras, represses cGAS-Sting signalling in lung adenocarcinoma

Cholesterol metabolism is abnormally active in tumour cells. Metabolic enzymes related to cholesterol metabolism are upregulated in tumours, but their nonmetabolic functions remain unclear. We found that MVK (mevalonate kinase) is upregulated in lung adenocarcinoma tissues vs. normal tissues and that its expression can be induced by constitutively activated Kras. By investigating the molecular mechanisms involved, we discovered that MVK interacts with TBK1, inhibiting TBK1 phosphorylation and thereby suppressing cGAS-Sting signalling. In addition, we found a negative correlation between MVK expression and CD8+ T-cell infiltration via a public database analysis. In summary, our study demonstrates the importance of the nonmetabolic function of MVK in modifying the immunological milieu and provides new targets for lung adenocarcinoma therapy.

Long-chain chlorinated paraffins (LCCPs) exposure causes senescence and inflammatory damage in cardiomyocytes.

Humans can be exposed to LCCPs through air and diet, leading to their accumulation in the body. Given the significance of understanding potential health risks, a thorough investigation into the detrimental health impacts of LCCPs is paramount. In this study, we conducted a series of experiments to investigate the effects of LCCPs on cardiomyocytes, employing techniques such as flow cytometry, western-blot, indirect immunofluorescence, and confocal microscopy. We initially observed that LCCPs caused senescence damage to cardiomyocytes. Under the stimulation of LCCPs, the number of SA-β-Gal positive cardiomyocytes increased, along with an elevation in the protein expression levels of cellular senescence markers (p21, p16). The cell cycle was arrested in the S phase. Subsequently, we observed that LCCPs also induced an increase in ROS and inflammatory cytokines (IL-6, IL-8, TNF-α), as well as a decrease in MMP in cardiomyocytes. Mechanistic studies revealed that LCCPs activated the innate immune response pathway-cGAS-STING pathway, and the cellular senescence damage caused by LCCPs was alleviated upon the addition of a cGAS-STING inhibitor. In conclusion, our findings suggest that LCCPs can induce aging damage in cardiomyocytes by activating the cGAS-STING signaling pathway. This study indicates that LCCPs possesses potential cardiotoxicity and offers necessary experimental data for their rational and regulated utilization.

Genetic deficiency or pharmacological inhibition of cGAS-STING signalling suppresses kidney inflammation and fibrosis.

Chronic kidney disease (CKD) is characterised by inflammation, which can lead to tubular atrophy and fibrosis. The molecular mechanisms are not well understood. In this study, we investigated the functional role of the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signalling in renal inflammation and fibrosis. Mice with global cGAS deficiency or global or myeloid cell-specific STING deficiency or wild-type mice treated with RU.521, a selective cGAS inhibitor, were used to examine the role of cGAS-STING signalling in renal inflammation and fibrosis in a preclinical model of obstructive nephropathy in vivo. Bone marrow-derived macrophages were used to determine whether tubular epithelial cell-derived DNA can activate cGAS-STING signalling in vitro. Following obstructive injury, cGAS-STING signalling was activated in the kidneys during the development of renal fibrosis. Mice with deficiency of cGAS or STING exhibited significantly less macrophage proinflammatory activation, myofibroblast formation, total collagen deposition, and extracellular matrix (ECM) protein production in the kidneys following obstructive injury. Pharmacological inhibition of cGAS with RU.521 reduced macrophage proinflammatory activation, suppressed myofibroblast formation, and attenuated kidney fibrosis following obstructive injury. Mechanistically, cGAS-STING signalling in macrophages is activated by double-stranded DNA released from damaged tubular epithelial cells, which induces inflammatory responses. Our study identifies the cGAS-STING signalling pathway as a critical regulator of macrophage proinflammatory activation during the development of renal fibrosis. Therefore, inhibition of cGAS-STING signalling may represent a novel therapeutic strategy for CKD.

Activation of the cGAS-sting Pathway Mediated by Nanocomplexes for Tumor Therapy.

cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway is an natural immune response signaling pathway in the human body that is essential for sensing abnormal DNA aggregation in the cell. When the cGAS protein senses abnormal or damaged DNA, it forms a second messenger called cyclic dinucleotide (cGAMP). The cycled dinucleotide will activate the downstream STING protein, thereby inducing the expression of inflammatory cytokines such as type I interferon, which binds to receptors on its own cell membrane and ultimately initiates multiple immune response pathways. This signaling pathway plays an important immune role in antimicrobial and antitumor functions, etc. so the development of drugs targeting this signaling pathway has important clinical application value. In recent years nanocomplexes based cGAS-STING signaling pathway activation and inhibition treatments have been gradually developed. In this review, on the basis of elaborating the main activation mechanism of the cGAS-STING pathway, we further introduced the nanocomplexes that effectively activate the cGAS-STING pathway, focusing on the composition, types and applications of the nanocomplexes. In addition, we discussed the key challenges and future research directions of the way that stimulating the cGAS-STING signaling pathway in the form of nanocomplexes to activate immuno-tumor therapy. Our work aims to provide a better understanding of the progress of nanotherapeutics in the cGAS-STING pathway, providing a promising anti-tumor therapeutic strategy.

Agonists Targeting the cGAS-STING Signaling Pathway and Their Applications in Cancer Therapy

The cyclic GMP-AMP synthase (cGAS) serves as a pivotal component of the immune system, playing a crucial role in regulating the innate immune response elicited by both exogenous and endogenous DNA. This enzyme recognizes the aberrant presence of DNA in the cytoplasm, subsequently activating the signaling pathway mediated by the stimulator of interferon genes (STING) and thereby fulfilling a critical role in immune response mechanisms. This review delineates the mechanisms of the cGAS-STING pathway and elucidates the small-molecule agonists targeting STING, along with their combined applications in various tumor treatment strategies. The aim of this review is to provide a valuable reference framework and insights for ongoing research in related fields.

Liver-Secreted Extracellular Vesicles Promote Cirrhosis-Associated Skeletal Muscle Injury Through mtDNA-cGAS/STING Axis.

Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA-enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS-STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS-STING signaling and its-mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis-induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV-mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA-enriched EVs. This study reveals that injured hepatocyte-derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis-associated skeletal muscle atrophy.

Laminaran potentiates cGAS-STING signaling to enhance antiviral responses.

Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway, an essential element in the innate antiviral immune responses, has emerged as a key component of innate immune system to modulate type I IFNs production and response by recognizing both exogenous and endogenous DNA. Although some cGAS-STING signaling small molecule agonists have been developed, there are few natural polysaccharides reported to activate cGAS-STING signaling for the treatment of infectious diseases. Here, we reported that Laminaran, a low molecular weight β-glucan storage polysaccharide present in brown algae, potentiates cGAS-STING signaling to promote type I IFNs production and antiviral response. Laminaran enhanced cGAS-STING signaling mediated type I IFNs production and response both in human and murine cells upon HSV-1 infection or DNA mimics stimulation. Importantly, we found that Laminaran markedly inhibited Herpes simplex virus-1 (HSV-1) induced death and inflammatory responses and increased the induction of type I IFNs in C57BL/6J mice. Mechanistically, we found Laminaran inhibited autophagy and suppressed STING autophagic degradation to positively regulate cGAS-STING signaling response. Taken together, we uncovered the function of Laminaran in DNA triggered innate immunity by enhancing cGAS-STING signaling response. Laminaran might be a potential therapeutic candidate for viral infectious diseases.

Regulation of cGAS-STING signalling and its diversity of cellular outcomes.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway, which recognizes both pathogen DNA and host-derived DNA, has emerged as a crucial component of the innate immune system, having important roles in antimicrobial defence, inflammatory disease, ageing, autoimmunity and cancer. Recent work suggests that the regulation of cGAS-STING signalling is complex and sophisticated. In this Review, we describe recent insights from structural studies that have helped to elucidate the molecular mechanisms of the cGAS-STING signalling cascade and we discuss how the cGAS-STING pathway is regulated by both activating and inhibitory factors. Furthermore, we summarize the newly emerging understanding of crosstalk between cGAS-STING signalling and other signalling pathways and provide examples to highlight the wide variety of cellular processes in which cGAS-STING signalling is involved, including autophagy, metabolism, ageing, inflammation and tumorigenesis.

In situ self-reassembling nanosystem enhances PD-L1 blockade for cancer immunotherapy

Although immune checkpoint inhibitors (ICIs) have made great progress in cancer treatment, their off-tumor distribution, low affinity of traditional ICIs and insufficient T cells infiltration at tumor site limit immunotherapeutic efficacy. Herein, we engineer a highly specific and effective PD-L1 inhibitor (PEC) that modulates the level of binding sites with PD-L1. Specifically, PEC is a hybrid system composed of E. coli membrane expressing PD-L1 binding protein and cancer cell membrane. Notably, PEC can target the tumor site, produce oxygen in response to H2O2, rupture into membrane fragments, and reassemble to form vesicles retaining the PD-L1 binding protein. Through in situ fracture and reassembly, PEC transforms from a hybrid membrane to a single E. coli membrane, leading to the increased density of PD-L1 binding protein. Consequently, the reassembled vesicles can bind to more PD-L1 on tumor cells and induce its degradation in lysosomes. Furthermore, the cGAS-STING signaling activators HZD is encapsulated into PEC to promote T cells infiltration. We demonstrate that PEC@HZD achieves sequential T cells recruitment and functional enhancement, thus stimulating a powerful antitumor immune response. This work provides a new perspective on tailoring ICIs to improve cancer immunotherapy.

The potential of melatonin in sepsis-associated acute kidney injury: Mitochondrial protection and cGAS-STING signaling pathway.

Melatonin (Mel) is known for various biological function, such as antioxidant and anti-inflammatory capabilities, as well as its ability to modulate immune responses, which can protect mitochondria and improve the prognosis of sepsis-associated acute kidney injury (SA-AKI). However, there is a multitude of theories regarding how Mel exerts its immune-modulating functions, with no consensus reached as of yet. We propose the protective effects of Mel on mitochondria are closely related to the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in the immune-inflammatory response. We intraperitoneally injected H151 and Mel into SA-AKI mouse models to interfere the cGAS-STING signaling pathway. By comparing behavioral, pathological, and molecular biology results, we discovered that Mel could reduce cGAS-STING signaling pathway while greatly relieving kidney damage and function. In addition, Mel-treated mice showed a significant increase in autophagosome formations, which might be linked to the cGAS-STING signaling pathway. Our findings suggest that Mel protection on kidney injury in SA-AKI mice is partially attributed to the inhibition of the cGAS-STING signaling pathway.

Nanodelivery of arsenic trioxide induces macrophage-governed cGAS-STING signaling to remodel immune microenvironment in hepatocellular carcinoma

Nanodelivery of arsenic trioxide induces macrophage-governed cGAS-STING signaling to remodel immune microenvironment in hepatocellular carcinoma

Homogeneous and bioluminescent biochemical and cellular assay for monitoring cGAMP and enzymes that generate and degrade cGAMP

The cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) signaling pathway is considered an essential pattern recognition and effector pathway in the natural immune system and is mainly responsible for recognizing DNA molecules present in the cytoplasm and activating downstream signaling pathways to generate type I interferons (IFN-I) and other inflammatory factors. STING, a crucial junction protein in the innate immune system, exerts an essential role in host resistance to external pathogen invasion. The DNA introduced by pathogens or tumors is recognized by the cytoplasmic nucleic acid receptor cGAS, and a second messenger, cGAMP, is generated using intracellular guanosine triphosphate (GTP) and adenosine triphosphate (ATP). Furthermore, cellular and extracellular cGAMP concentrations are also controlled by ENPP1, an enzyme that breaks down cGAMP to AMP and GMP. Therefore, the role of the cGAS-STING signaling pathway has generated great interest in inflammatory and cancer research. To advance our understanding of innate immune system and in particular the STING pathway, we have developed a homogeneous, bioluminescent cGAMP detection assay that is very sensitive and highly selective against other nucleotides, cyclic nucleotides, and dicyclic nucleotides. The assay can be also used to monitor the activity of cGAS and ENPP1 to enable the development of inhibitors of both enzymes which might be used for therapeutic applications.

Ferritinophagy promotes microglia ferroptosis to aggravate neuroinflammation induced by cerebral ischemia-reperfusion injury via activation of the cGAS-STING signaling pathway.

Cerebral ischemia-reperfusion injury (CIRI) is a common and serious complication of reperfusion therapy in patients with ischemic stroke (IS). The regulation of microglia-mediated neuroinflammation to control CIRI has garnered considerable attention. The balance of iron metabolism is key to maintaining the physiological functions of microglia. Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy, an important pathway in regulating iron metabolism, is a promising intervention target. However, studies on the impacts of ferritinophagy on microglia-mediated neuroinflammation are lacking. This study aimed to identify potential treatments for CIRI-induced neuroinflammation by focusing on ferritinophagy and the specific mechanisms whereby iron metabolism regulates microglia-mediated neuroinflammation. CIRI induced the activation of ferritinophagy in microglia, characterized by the upregulation of NCOA4, downregulation of Ferritin Heavy Chain 1 (FTH1), and increased intracellular iron levels. This activation contributes to increased ferroptosis, oxidative stress, and the release of inflammatory factors. Silencing NCOA4 or application of the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively suppressed the CIRI-induced damage in vivo and in vitro. While Fer-1 addition did not inhibit the CIRI-activated ferritinophagy, it did partially reverse the alleviation of NCOA4 depletion-induced neuroinflammation, suggesting that ferroptosis is an essential intermediate step in ferritinophagy-induced neuroinflammatory damage. Furthermore, using IS-related transcriptomic data, the cGAS-STING pathway was identified as a crucial mechanism connecting ferritinophagy and ferroptosis. Specific inhibition of the cGAS-STING pathway reduced ferritinophagy-induced ferroptosis and neuroinflammation. In summary, our results indicated that ferritinophagy activates the cGAS-STING signaling pathway, which promotes the inflammatory response and oxidative stress in microglia in a ferroptosis-dependent manner, thereby exacerbating CIRI-induced neuroinflammation. These findings provide theoretical support for the clinical treatment of CIRI.

The role of cGAS-STING signaling pathway in ferroptosis.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been identified as a crucial mechanism in antiviral defense and innate immunity pathway. Ferroptosis, characterized by iron dependence and lipid peroxidation, represents a specialized form of cell death. A burgeoning collection of studies has demonstrated that the cGAS-STING signaling pathway participates in the homeostatic regulation of the organism by modulating ferroptosis-associated enzyme activity or gene expression. Consequently, elucidating the specific roles of the STING signaling pathway and ferroptosis in vivo is vital for targeted disease intervention. This review systematically examines the interactions between the cGAS-STING signaling pathway and ferroptosis, highlighting their influence on disease progression in the contexts of inflammation, injury, and cancerous cell dynamics. Understanding these interactions may provide novel therapeutic strategies. The STING pathway has been implicated in the regulation of various cell death mechanisms, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis. Our focus primarily addresses the role and mechanism of the cGAS-STING signaling pathway and ferroptosis in diseases, limiting discussion of other cell death modalities and precluding a comprehensive overview of the pathway's additional functions.

Liangxue Jiedu Huayu Formula improves liver function of mice with acute-on-chronic liver failure by inhibiting excessive activation of the cGAS-STING signaling pathway

To explore the role of the cGAS-STING signaling pathway in the therapeutic mechanism of Liangxue Jiedu Huayu Formula (LXJDHYF) for acute-on-chronic liver failure (ACLF) in mice. Thirty C57BL/6 mice were randomly divided into blank control group, model group, low- and high-dose LXJDHYF groups, and H151 (a specific cGAS-STING pathway inhibitor) group (n=6). In all but the control group, the mice were treated with CCl4 to induce liver cirrhosis followed by intraperitoneal injections of lipopolysaccharide and D-amino galactose to establish mouse models of ACLF. After the treatments, the mouse livers were collected for HE and TUNEL staining, and serum levels of ALT, AST and TBil were determined. In bone marrow-derived macrophages (BMDMs) and liver tissues of ACLF mice, the expressions of cGAS-STING signaling pathway-related mRNAs including IFN‑β, ISG15, IL-6 and TNF-α were determined with RT-qPCR, and the phosphorylation levels of IRF3 and STING proteins were investigated using Western blotting. Compared with the mice in the model group, the LXJDHYF-treated mice exhibited milder hepatocyte necrosis and inflammatory cell infiltration in the liver with significantly reduced hepatocyte apoptosis. LXJDHYF treatment also significantly lowered serum levels of ALT, AST, TBil, IL-6 and TNF-α in ACLF mice and effectively suppressed the expressions of cGAS-STING signaling pathway-related mRNA in both the BMDMs and the liver tissues and the phosphorylation of IRF3 and STING proteins in the BMDMs. LXJDHYF can significantly improve liver function and attenuate inflammation in ACLF mice possibly by inhibiting excessive activation of the cGAS-STING signaling pathway.

Antigen-presenting cell activation requires intrinsic and extrinsic STING signaling after the phagocytosis of DNA-damaged cells.

Antigen-presenting cells (APCs) are readily activated after phagocytosing infected or DNA-damaged cells but not normal apoptotic cells for reasons that are not well understood. Here, we demonstrate that after DNA damage events, cytosolic dsDNA species trigger intrinsic STING signaling and the production of key immunogenic proteins, including CCL5, which renders such cells capable of APC activation upon phagocytosis. These events involve the generation of immunogenic STING-inducible endosomal vesicles (SIEVEs) additionally comprising critical autophagy-associated proteins associated with cytosolic DNA species. After phagocytosis, extrinsic cGAS-STING signaling is triggered via engulfed, immunogenic transactivating DNA vesicles resulting in APC stimulation. These results help explain how APCs are predominantly activated by DNA-damaged or infected cells in contrast with normal apoptotic cells and suggest that reconstitution of STING signaling or key inducible genes in cGAS-STING-defective malignancies could substantially augment cancer immunotherapies.

The Role of the cGAS/STING Pathway in Arsenic-Induced Neurotoxicity: Insights from the Crosstalk Between Astrocytes and Neurons.

Arsenic is a detrimental environmental toxicant linked to neurological damage; however, the mechanisms involved remain incompletely understood. Chronic proinflammatory responses are thought to play a central role in arsenic-induced neurotoxicity. Astrocytes, which are the predominant glial cells in the central nervous system (CNS), release significant amounts of proinflammatory cytokines upon overactivation. However, the molecular mechanisms driving this response remain to be elucidated. This study aimed to elucidate the mechanisms underlying arsenic-induced astrocyte activation and the subsequent neuronal damage, both in vivo and in vitro. In a rat model of arsenic exposure, significant neuropathological damage was detected in the CA3 region of the hippocampus. Specifically, markers of astrocyte activation, such as glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS), as well as the inflammatory cytokine interleukin (IL)-1β, were significantly upregulated, and apoptosis was markedly increased, indicating neurotoxic damage. Furthermore, in vitro experiments revealed that arsenic exposure induced substantial upregulation of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), GFAP, iNOS, and IL-1β in astrocytes, accompanied by an increase in IL-1β secretion into the culture supernatant. In addition, co-culturing neurons with conditioned medium from arsenic-exposed astrocytes resulted in significant neuronal apoptosis. Importantly, the cGAS-STING pathway inhibitor H-151 effectively suppressed the arsenic-induced astrocyte activation and IL-1β secretion, while also reducing neuronal apoptosis in the conditioned medium. Collectively, these results indicate that arsenic exposure activates the cGAS-STING signaling pathway in astrocytes, enhancing proinflammatory activation and IL-1β expression, which in turn mediates neuronal apoptosis, representing a critical mechanism underlying arsenic-induced neurotoxicity.

Cordycepin ameliorates autoimmunity by promoting STING degradation via autophagy pathway.

Stimulator of interferon response cGAMP interactor 1 (STING), a central hub protein of cyclic GMP-AMP synthase (cGAS)-STING signalling pathway, has a crucial role in regulating type I interferons (IFNs) production and response. Recent studies indicate that excessive activation of STING is strongly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Searching immunomodulators that negatively regulate STING might greatly contribute to the suppression of autoimmunity. The peripheral blood mononuclear cells (PBMCs) of SLE patients, Hela cells, L929 cells and bone marrow-derived macrophages (BMDMs) from mice were used as in vitro models. While, Trex1 KO mouse autoimmune disease model was used as in vivo model. After treatment with cordycepin, a nucleoside from Cordyceps mushrooms, type I IFNs production and response were determined by western blotting, real-time polymerase chain reaction (PCR), dual-luciferase assay, enzyme-linked immunosorbent assay (ELISA), haematoxylin-eosin staining and RNA-seq. Cordycepin inhibited type I IFNs production and response in human and murine systems following cGAS-STING signalling activation. Importantly, cordycepin markedly attenuates the autoinflammatory and autoimmune responses in Trex1 KO BMDMs and Trex1 KO mice. Furthermore, cordycepin effectively suppressed the production of type I IFNs and interferon-stimulated genes (ISGs) in the PBMCs of SLE patients. Mechanistically, cordycepin promoted STING degradation via autophagy pathway upon DNA stimulation. This study shows that cordycepin promotes STING autophagic degradation to alleviate autoimmunity upon DNA stimulation. Cordycepin might be a potential therapeutic candidate for alleviating aberrant type I IFNs in autoimmune and autoinflammatory diseases.

H2S-Scavenging Hydrogel Alleviating Mitochondria Damage to Control Periodontitis

H2S, as a typical metabolite of periodontal pathogens, exhibits a clear positive correlation with the occurrence and development of periodontitis. H2S at physiological concentrations can regulate many biological processes. However, excess H2S in the periodontal pocket can trigger secretion of proinflammatory cytokines, cause oxidative stress, and result in mitochondrial damage and cell death in human gingival fibroblasts, exacerbating periodontitis development and periodontal tissue destruction. Worse, H2S facilitates bacteria survival and proliferation by maintaining bacterial redox balance and enhancing antibiotic resistance. Unfortunately, scavenging H2S during periodontitis treatment is usually ignored. Herein, a kind of hyaluronic acid methacryloyl/ZnO (HMZ) composite hydrogel with an H2S-scavenging ability was prepared to enhance periodontitis treatment. The HMZ hydrogel possessed good injectability and cytocompatibility and was able to remove H2S by a reaction with ZnO. As a result, the HMZ hydrogel was able to increase cell viability from 13% to 120% for human gingival fibroblasts and 22% to 94% for human periodontal ligament fibroblasts at 48 h, restore mitochondrial homeostasis, and alleviate cGAS-STING signaling pathway–mediated inflammation. Meanwhile, the HMZ hydrogel showed satisfactory antibacterial properties and efficiency of plaque biofilm removal. The in vivo results further confirmed that HMZ hydrogel decreased the concentration of H2S within the periodontal pocket from 0.7 to 0.8 mM to the normal level (0.3 to 0.4 mM), killed the bacteria in the periodontal tissues, inhibited osteoclast activity, relieved excess inflammation, and decreased the vertical distance between the cementoenamel junction and the alveolar bone crest from 1,175 µm to 798 µm on the 7th day and from 1,075 µm to 693 µm on the 14th day, achieving efficient periodontal bone regeneration. In brief, an H2S scavenging-based promising strategy was developed to enhance the therapeutic efficiency of periodontitis.