Inflammation最新文献

{"title":"CLICs Inhibitor IAA94 Alleviates Inflammation and Injury in Septic Liver by Preventing Pyroptosis in Macrophages.","authors":"Jing Liu, Jingwen Hu, Xulei Yao, Mengting Xu, Aini Yuan, Jianan Guo, Cui Wang, Yifei Le, Xingyu Yuan, Dezhao Lu","doi":"10.1007/s10753-025-02304-6","DOIUrl":"https://doi.org/10.1007/s10753-025-02304-6","url":null,"abstract":"<p><p>Macrophage pyroptosis represents a pivotal mechanism underlying acute liver injury during sepsis. Chloride intracellular channel proteins (CLICs) have been linked to inflammatory reflexes, with IAA94 serving as an inhibitor of channel formation characteristic of CLICs. In a mouse model, IAA94 demonstrated efficacy in reducing pro-inflammatory cytokines in liver tissues, decreasing macrophage in the liver, inhibiting the development of the pro-fibrosis phenotype, and alleviating tissue injury. Additionally, IAA94 exhibited inhibitory effects on the activation of NLRP3 inflammasome, leading to the suppression of pyroptosis in J774A.1 cells and the liver. Additionally, IAA94 was observed to impede the interaction between NEK7 and NLRP3. Furthermore, it was observed that the conditioned medium of pyroptotic macrophages treated with IAA94 induced an attenuated inflammatory response in hepatocytes in comparison to that induced by the conditioned medium of pyroptotic macrophages. However, NLRP3 overexpression impeded the beneficial effects of IAA94. In conclusion, IAA94 has the capacity to impede NLRP3 inflammasome formation-mediated pyroptosis by blocking CLICs-mediated chloride efflux and the inhibition of NEK7-NLRP3 interactions, thereby establishing CLICs as a promising therapeutic target against liver inflammation.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TFAM Deficiency Triggers mtDNA Leakage and cGAS-STING-Mediated Intestinal Ischemia-Reperfusion Injury.","authors":"Ke Ding, Lele Zhang, Yiguo Zhang, Yixin Jing, Huiyang Liao, Rong Chen, Qingtao Meng","doi":"10.1007/s10753-025-02302-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02302-8","url":null,"abstract":"<p><p>Intestinal Ischemia-Reperfusion (IIR) injury is a common clinical pathophysiological condition, yet the complex molecular mechanisms underlying its pathology remain incompletely understood. This study aims to explore the precise molecular mechanisms of IIR injury, with a focus on the role of the cGAS-STING signaling pathway. Using a mouse IIR model and hypoxia/reoxygenation (HR) model in HT-29 cells and small intestinal organoids, we observed that IIR significantly induces oxidative stress and activates the cGAS-STING pathway, which is associated with exacerbated small intestinal tissue damage and enhanced inflammatory responses. Further investigation revealed that mitochondrial DNA (mtDNA) leakage is a critical trigger for the activation of the cGAS-STING pathway. The introduction of exogenous mtDNA into cells activated the STING pathway and exacerbated cellular damage. In contrast, the depletion of intracellular mtDNA effectively suppressed HR-induced activation of the cGAS-STING pathway. Mechanistically, we found that IIR downregulates mitochondrial transcription factor A (TFAM), which subsequently affects mtDNA stability, promoting the release of mtDNA into the cytoplasm and triggering the cGAS-STING pathway. Overexpression of TFAM stabilized mtDNA, reduced the accumulation of cytoplasmic mtDNA, inhibited cGAS-STING pathway activation, and alleviated cellular damage. Moreover, STING-deficient mice exhibited reduced inflammation, less tissue damage, and improved survival rates following IIR, highlighting the critical role of the STING pathway in IIR-induced injury. Our findings elucidate the close association between oxidative stress, inflammation, and cGAS-STING pathway activation in IIR. mtDNA leakage and TFAM downregulation are key mechanisms driving this activation. Importantly, TFAM plays a crucial role in stabilizing mtDNA and reducing mtDNA leakage during IIR. These results not only deepen our understanding of the molecular pathogenesis of IIR injury but also provide potential therapeutic strategies targeting the cGAS-STING pathway for treating IIR-related diseases.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Troxerutin on Oxidative Stress, Inflammation and Galectin- 3 Expression in Intracerebroventricular Kainic Acid-Induced Neurotoxicity.","authors":"Mehmet Demir, Hulya Elbe, Dilan Cetinavci, Ercan Saruhan","doi":"10.1007/s10753-025-02301-9","DOIUrl":"https://doi.org/10.1007/s10753-025-02301-9","url":null,"abstract":"<p><p>Excitotoxicity caused by excessive concentration of the excitatory neurotransmitter glutamate causes neuronal cell death and promotes neurodegenerative disorders. The neuroexcitant neurotoxin kainic acid (KA) induces excitotoxicity, leading to neuronal death via oxidative stress and inflammation, and its experimental use is widespread. This study was designed to determine the protective effect of Troxerutin (TXR) and its relationship with Galectin-3 (Gal-3) in experimental excitotoxicity with neuroinflammation and oxidative stress. Fifty male Wistar rats were divided into five groups (n = 10): Control group rats received intraperitoneal (ip) normal saline for 6 days. Sham group rats received a single dose of intracerebroventricular (icv) normal saline on the first day. KA group rats were treated with a single dose of KA; icv-0.5 μg/μl). TXR group rats treated with TXR for 6 days: ip-100 mg/kg) and KA + TXR group rats treated with KA (single dose) and TXR (6 days). It was observed that malondialdehyde (MDA) and interleukin-1β (IL-1β) levels increased and reduced glutathione (GSH) levels decreased in the cerebral cortex of rats with KA neurotoxicity. TXR treatment caused a significant improvement in MDA and GSH levels and a significant decrease in IL-1β levels in rats with the excitotoxicity model. Gal-3 expressions in the hippocampus and cerebellum increased in KA-treated rats, whereas TXR treatment decreased Gal-3 expressions. In addition, histopathological changes caused by KA administration showed improvement in TXR-treated groups. In conclusion, the findings showed that TXR treatment attenuated KA-induced neurotoxicity by reducing oxidative tissue damage, inflammatory response and Gal-3 expression.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT6 Overexpression Enhances Diabetic Foot Ulcer Healing via Nrf2 Pathway Activation.","authors":"Li Wei, Mengyang Kang, Guofeng Zhang, Yan Meng, Hao Qin","doi":"10.1007/s10753-025-02297-2","DOIUrl":"https://doi.org/10.1007/s10753-025-02297-2","url":null,"abstract":"<p><p>Sirtuin-6 (SIRT6) has a pivotal role in a wide array of cellular biological functions and is linked to the progression of various diseases. Previous findings have identified SIRT6 as a protective modulator against numerous diabetic complications. However, whether SIRT6 exerts a protective role in diabetic foot ulcer (DFU) remains unstudied. This work established a rat model of DFU and evaluated the possible role of SIRT6 in mediating the wound healing in DFU. Marked reductions in SIRT6 levels were observed in wound samples from DFU patients and rats. Increasing SIRT6 expression in wound tissues remarkably decreased wound area, accelerated epithelialisation, increased collagen deposition and improved angiogenesis. Moreover, up-modulation of SIRT6 relieved the oxidative stress and inflammation in DFU rats. The increase of SIRT6 in cultured vascular endothelial cells restrained cell apoptosis, oxidative stress and inflammation elicited by high glucose (HG). HG-impaired migration capacity and angiogenesis of vascular endothelial cells was also recovered by increasing SIRT6 expression. Mechanism research revealed that SIRT6 overexpression reinforced the activation of the Nrf2 pathway in wound tissues of DFU rats and HG-exposed vascular endothelial cells. Pharmacological suppression of Nrf2 reversed the protective effect of SIRT6 overexpression on HG-triggered endothelial dysfunction. The findings of this work indicate that the positive role of SIRT6 in DFU wound healing is related to Nrf2 activation which contributes to the suppression of oxidative stress and inflammation and the improvement of angiogenesis in vascular endothelial cells. This study highlights the previously unaddressed role of SIRT6 in DFU wound healing, providing novel insights into its protective functions. The findings hold significant clinical value by identifying SIRT6 as a promising therapeutic target for improving DFU wound healing.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MLKL-Mediated Necroptosis Predominantly Contributes to Immune-Associated Myocardial Damage.","authors":"Jinglei Sun, Wenting Wu, Yi Wang, Jiali Zhang, Suhua Qiu, Zhengkun Guan, Chenxia Shi, Jingtao Ma, Yanfang Xu","doi":"10.1007/s10753-025-02298-1","DOIUrl":"https://doi.org/10.1007/s10753-025-02298-1","url":null,"abstract":"<p><p>Activated T cells and macrophages play a critical role in immune-associated myocarditis. However, the molecular and cellular mechanisms driving cardiomyocyte damage by immune cells remain poorly understood. In this study, we co-cultured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with activated human peripheral blood mononuclear cells (aPBMCs) to recapitulate myocardial infiltration of immune cells. Our results demonstrated that aPBMCs induced hiPSC-CMs death in a dose- and time-dependent manner. Transcriptome analysis revealed the activation of several death pathways, including pyroptosis, apoptosis and necroptosis. The time course of immunofluorescence staining of key proteins related to different death pathways demonstrated that necroptosis was the earliest activated pathway. Pharmacological blockade of necroptosis by targeting mixed lineage kinase domain-like protein (MLKL), receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein RIPK1 kinase 3 (RIPK3) protected hiPSC-CMs against injury induced by aPBMCs, while inhibitors of pyroptosis and apoptosis showed no protective effect. Moreover, MLKL knockdown in hiPSC-CMs prevented cell death due to aPBMCs challenge. Additionally, we validated the cardioprotective effects of blocking necroptosis in a mouse model of immune checkpoint inhibitors (ICIs)-related myocarditis using a combination of long-term anti-programmed cell death 1 (PD- 1) and anti-cytotoxic T-lymphocyte antigen- 4 (CTLA- 4) antibodies. ICIs led to elevation of myocardial injury markers in serum and activated immune cells infiltration. Furthermore, in vivo administration of a MLKL inhibitor prevented ICIs-induced myocardial injury. In conclusion, our findings suggested that MLKL-mediated necroptosis predominantly contributed to cardiomyocyte death resulting from activated immune cells. Suppressing necroptosis may be an effective therapeutic approach against myocardial damage in myocarditis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Protective Effects of Vanillic Acid on LPS-induced Acute Lung Injury by Inhibiting STIM1-mediated NLRP3 Inflammasome Activation.","authors":"Lei Wang, Hai-Dong Li, Xia Sun, Jia-Hui Ni, Gui-Ze Feng, Xiao-Yan Shen, Hong-Bo Weng, Hao Fang","doi":"10.1007/s10753-025-02293-6","DOIUrl":"https://doi.org/10.1007/s10753-025-02293-6","url":null,"abstract":"<p><p>Acute lung injury (ALI), which can progress to acute respiratory distress syndrome (ARDS), has inflammation as a crucial factor, especially the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome involvement. Stromal interaction molecule 1 (STIM1) can block NLRP3 activation, but the mechanism is unclear. Vanillic acid, possessing anti-inflammatory properties, has a role in acute lung injury (ALI) whose specific mechanism remains unclear. This study aimed to investigate the effectiveness of vanillic acid in ALI induced by lipopolysaccharides (LPS) and to elucidate the potential mechanisms. In vitro and in vivo experiments were conducted using cells and a mouse model to find out the impact and underlying mechanisms. We found that vanillic acid demonstrated significant inhibition of IL-1β and IL-18 release triggered by LPS and nigericin in J774A.1 cells. The in vivo findings indicated that vanillic acid not only mitigated acute lung injury but also suppressed NLRP3 inflammasome activation in mice. Mechanistically, vanillic acid inhibited the LPS-induced increase in STIM1 expression through the lysosomal degradation pathway. The reduced STIM1 expression diminished intracellular Ca²⁺ levels, thereby suppressing inflammasome activation and impeding the cleavage and maturation of Caspase-1 and GSDMD, and eventually attenuating cell pyroptosis. Vanillic acid exerts its inhibitory effects on NLRP3 inflammasome activation by promoting STIM1 degradation, thereby ameliorates ALI through impeding NLRP3-GSDMD mediated pyroptosis. The STIM1-NLRP3 signaling axis represents a promising avenue for potential therapeutic interventions in ALI.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Inflammatory Axis of LncRNA Ftx/miR-382-5p/NRG1 in the Differential Diagnosis and Prognosis of Multiple Sclerosis and Neuromyelitis Optica.","authors":"Nadia Mangoud, Mohamed I Hegazy, Shady Estfanous, Sahar A Ali","doi":"10.1007/s10753-025-02284-7","DOIUrl":"https://doi.org/10.1007/s10753-025-02284-7","url":null,"abstract":"<p><p>Multiple sclerosis (MS) and Neuromyelitis Optica (NMO) are immune-related CNS inflammatory diseases that often present with overlapping clinical symptoms, leading to frequent misdiagnosis, particularly in aquaporin-4 seronegative NMO patients. Identifying the underlying mechanisms of these diseases is critical for discovering biomarkers that enable timely diagnosis and effective treatment. This study included 252 participants, divided into four groups. Group I (Relapsing-Remitting MS: RRMS group), Group II (Secondary Progressive MS: SPMS group), Group III (NMO group), and Group IV (Healthy controls). Blood samples were collected from all participants to measure the expression levels of Neuregulin-1 (NRG1), lncRNA Ftx, and miR-382-5p. The results showed that NRG1 levels were significantly lower in the RRMS, SPMS, NMO groups compared to healthy controls, with the most pronounced reduction observed in NMO, suggesting NRG1 may serve as a potential biomarker for differentiating NMO from MS, especially in cases where traditional diagnostic criteria are inconclusive. lncRNA Ftx, a sponge for miR-382-5p, exhibited an opposite trend to miR-382-5p and was significantly downregulated in NMO compared to MS, SPMS, RRMS, and healthy controls, suggesting its potential as a promising biomarker. Our findings highlight the potential of NRG1, lncRNA Ftx, and miR-382-5p expression as diagnostic, screening, and prognostic biomarkers, as well as tools for the differential diagnosis of NMO and MS.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR/Cas9-Mediated Knockout and Overexpression Studies Unveil the Role of PD-L1 in Immune Modulation in a Psoriasis-like Mouse Model.","authors":"Chunjie Gao, Yunxi Cai, Xinxin Wu, Jiankun Song, Qi Zheng, Mingxia Wang, Ying Luo, Yue Luo, Xiaoya Fei, Ying Zhang, Yang Yang, Le Kuai, Yi Ru, Seokgyeong Hong, Na Tian, Bin Li, Zhan Zhang","doi":"10.1007/s10753-025-02281-w","DOIUrl":"https://doi.org/10.1007/s10753-025-02281-w","url":null,"abstract":"<p><p>The role of programmed death-ligand 1 (PD-L1), an essential immune checkpoint protein, has garnered considerable interest in recent years due to its influence on immune responses, particularly inhibiting immature Th cells into Th17 cells. This study aims to examine the effect of PD-L1 on psoriasis progress, which is the condition characterized by an immune response dominated by Th17 cells. We constructed the PD-L1 knockout (PD-L1^KO) and overexpression (PD-L1^OE) mice through CRISPR/Cas9 technology to assess the impact of PD-L1 in an imiquimod (IMQ)-induced psoriasis-like mouse model. In comparison to IMQ, the ear thickness exhibited a reduction, the PASI score decreased, and HE sections revealed a thinning of the epidermal spines in PD-L1^OE mice. PD-L1^KO mice, however, showed opposite results. Moreover, immunohistochemical assessments of the skin lesion tissues demonstrated heightened epidermal proliferation and inflammatory infiltration in the PD-L1^KO group, accompanied by elevated tissue expression of proliferating cell nuclear antigen (PCNA), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p50, and F4/80 in comparison to IMQ-treated and WT mice. The absence of PD-L1 in IMQ-induced mice was found to intensify the immune response, as evidenced by heightened expression of phosphorylated signal transducers and activators of transcription 3 (pSTAT3) and CD3 in the affected tissues compared to both IMQ-treated and WT mice. According to our findings, PD-L1 plays important roles in inhibiting inflammation, proliferation, and regulating immune responses. Targeting PD-L1 may present a promising therapeutic strategy for the management of psoriasis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRK2 Mediates α-Synuclein-Induced Neuroinflammation and Ferroptosis through the p62-Keap1-Nrf2 Pathway in Parkinson's Disease.","authors":"Xinjie Liu, Zijian Zheng, Cheng Xue, Xiangrong Wang, Jianwei Li, Zheng Liu, Wenqiang Xin, Xinping Xu, Dongwei Zhou, Longping Yao, Guohui Lu","doi":"10.1007/s10753-025-02291-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02291-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the abnormal aggregation of α-synuclein (α-syn). Despite extensive research, the mechanisms underlying microglial-mediated neuroinflammation and ferroptosis in PD remain inadequately understood. In particular, the role of leucine-rich repeat kinase 2 (LRRK2) in microglial cells and its modulation of the p62-Keap1-Nrf2 signaling pathway warrant further investigation.In this study, we present novel findings demonstrating that LRRK2 regulates microglial neuroinflammation and ferroptosis through the p62-Keap1-Nrf2 signaling axis in the context of PD. Using α-syn-stimulated BV2 microglial cells, we found that LRRK2 inhibition significantly reduced the production of pro-inflammatory cytokines and enhanced the activation of the p62-Keap1-Nrf2 pathway, thereby mitigating ferroptosis and oxidative stress. Furthermore, conditioned medium from LRRK2-inhibited microglia conferred neuroprotective effects on cultured neurons, highlighting the therapeutic potential of targeting LRRK2 in microglia.Importantly, these in vitro findings were corroborated in the MPTP-induced PD mouse model, where LRRK2 inhibition led to diminished microglial activation, decreased apoptosis of midbrain dopaminergic neurons, and upregulation of the p62-Keap1-Nrf2 pathway.Our study fills a critical gap in understanding the microglial mechanisms mediated by LRRK2 and provides novel insights into the pathogenesis of PD. These findings suggest that targeting LRRK2 in microglia may represent a promising therapeutic strategy for PD.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Canonical STING-PERK Pathway Modulation of Cellular Senescence and Therapeutic Response in Sepsis-Associated Acute Kidney Injury.","authors":"Yuxin Dong, Guanghe Liu, Xiaonan Situ, Lei Xia, Tianyi Zhang, Xiangxi Zhu, Heng Jin, Yancun Liu, Songtao Shou","doi":"10.1007/s10753-024-02081-8","DOIUrl":"10.1007/s10753-024-02081-8","url":null,"abstract":"<p><p>Abstract-This study explored the role of the non-canonical STING-PERK signaling pathway in sepsis-associated acute kidney injury (SA-AKI). Gene expression data from the GEO database and serum STING protein levels in patients with SA-AKI were analyzed. An LPS-induced mouse model and an in vitro model using HK-2 cells were used to investigate the role of STING in SA-AKI. STING expression was suppressed using shRNA silencing technology and the STING inhibitor C176. Kidney function, inflammatory markers, apoptosis, and senescence were measured. The role of the STING-PERK pathway was investigated by silencing PERK in HK-2 cells and administering the PERK inhibitor GSK2606414. STING mRNA expression and serum STING protein levels were significantly higher in patients with SA-AKI. Suppressing STING expression improved kidney function, reduced inflammation, and inhibited apoptosis and senescence. Silencing PERK or administering GSK2606414 suppressed the inflammatory response, cell apoptosis, and senescence, suggesting that PERK is a downstream effector in the STING signaling pathway. The STING-PERK signaling pathway exacerbates cell senescence and apoptosis in SA-AKI. Inhibiting this pathway could provide potential therapeutic targets for SA-AKI treatment.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"696-712"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}