Asian Pacific Journal of Tropical Biomedicine
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2026
·Vol. 16
·期 6
·225
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IF 1.9
Zhang Rui,Zhou Yang,Xiao Ting,Gu Yan
Objective: To evaluate the effect of isorhamnetin on diabetic kidney disease and elucidate its underlying mechanisms. Methods: A high glucose-stimulated mouse podocyte (MPC-5) model was employed to evaluate the effects of isorhamnetin on podocyte injury, secretion of inflammatory cytokines, NLRP3 inflammasome activation, pyroptosis, mitochondrial function, cytosolic release of mtDNA, and activation of the cGAS-STING signaling pathway. Nigericin (an NLRP3 activator) and siRNA were used in combination to clarify the regulatory relationships between these pathways. Furthermore, a mouse model of diabetic kidney disease was established and treated with isorhamnetin via intragastric administration. Blood glucose and renal function parameters were measured, renal histopathological changes were examined, and alterations in podocyte marker proteins, inflammasome activation, pyroptosis, mitochondrial damage, and the cGAS-STING pathway in kidney tissues were analyzed. Results: Isorhamnetin alleviated high glucose-induced abnormalities in podocyte marker proteins and cellular injury. It also inhibited NLRP3 inflammasome activation, thereby attenuating pyroptosis. Furthermore, isorhamnetin stabilized mitochondrial membrane potential, decreased mitochondrial ROS production, suppressed excessive opening of the mitochondrial permeability transition pore, alleviated mitochondrial damage, and reduced cytosolic mtDNA release, which in turn suppressed activation of the cGAS-STING pathway. Knockdown of STING inhibited high glucose-induced NLRP3-dependent pyroptosis. Consistently, isorhamnetin improved renal function in mice with diabetic kidney disease, attenuated glomerulosclerosis and fibrosis, and markedly suppressed mitochondrial damage, mtDNA leakage, cGAS-STING activation, and NLRP3-mediated pyroptosis and inflammatory responses in renal tissues. Conclusions: Isorhamnetin treatment attenuates diabetic kidney disease by improving mitochondrial homeostasis and inhibiting the cGAS-STING/NLRP3 inflammasome pathway.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Pengfei Yang,Jie Zhang,Guanglei Ma,Songsong Zhi,Yi Chang,Lina Ding,Xiaoming Ma,Yuming Guo
Immunotherapy is a promising treatment strategy for tumors; however, its efficacy is limited by the complicated immunosuppressive tumor microenvironment (TME). Herein, we developed a simple drug-free bioactive multifunctional nanoplatform (named MnO 2 –CaS) that was sustainably degraded in a weakly acidic TME to release calcium ions (Ca 2+ ) and generate manganese ions (Mn 2+ ) and hydrogen sulfide (H 2 S). Mn 2+ activated and amplified the cyclic GMP-AMP (cGAMP) synthase stimulator of interferon gene (cGAS–STING) pathway and simultaneously produced oxygen to alleviate hypoxia. H 2 S, a therapeutic gas, not only induced mitochondrial damage but also prevented the extracellular efflux of Ca 2+ , leading to a sharp increase in Ca 2+ concentration in mitochondria. The abnormal intracellular Ca 2+ overload induced pyroptosis, disturbed mitochondrial respiration, and reduced metabolic oxygen consumption, thereby alleviating hypoxia and amplifying oxidative stress. Gasdermin-mediated pyroptosis facilitated mitochondrial DNA (mtDNA) release, further amplifying cGAS–STING pathway activation to induce robust antitumor immunity. In addition, the nanoplatform generated abundant reactive oxygen species (ROS) and depleted glutathione (GSH), inhibiting glutathione peroxidase 4 (GPX4) biosynthesis. This process exacerbated lipid peroxidation and induced ferroptosis. Altogether, the self-cascading immunomodulatory nanoplatform alleviated tumor hypoxia to mitigate immunosuppression and amplify pyroptosis-driven cGAS-STING pathway activation. The nanoplatform synergized with chemodynamic therapy (CDT) and ferroptosis to effectively suppress the growth and metastasis of both primary and distant tumors. This study provides a novel strategy for co-activating pyroptosis and cGAS–STING signaling in immunotherapy, offering insights for developing safe and effective immunotherapies for cancer treatment.
研究领域:
癌症免疫治疗
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纳米医学
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肿瘤微环境
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免疫代谢
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气体治疗
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活性氧信号传导
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PHYTOTHERAPY RESEARCH
·
2024
·
IF 6.1
Liu-Gen Li,Jun Hu,Ning Han,Nan-Nan Chen,Ting-Ting Yu,Tao Ren,Hua-Zhen Xu,Xing-Chun Peng,Xian-Yu Li,Tian-Qi Ma,Hao Chen,Lei Zhang,Xiao Chen,Mei-Fang Wang,Tong-Fei Li
Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.
研究领域:
肿瘤学
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免疫学
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药理学
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细胞生物学
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2023
·
IF 9.9
Xin Sun,Shiqing Zhang,Qianzhe Li,Mengyu Yang,Xiaonan Qiu,Beibei Yu,Cuixiu Wu,Zhaoliang Su,Fengyi Du,Miaomiao Zhang
Phototherapy can trigger immunogenic cell death of tumors in situ, whereas it is virtually impossible to eradicate the tumor due to the intrinsic resistance and inefficient anti-tumor immunity. To overcome these limitations, novel bimetallic infinite coordination nanopolymers (TA-Fe/ [email protected] NPs) were synthesized using model antigen ovalbumin (OVA) as a template to assemble tannic acid (TA) and bi-metal, supplemented with methylene blue (MB) surface absorption. The formulated TA-Fe/ [email protected] NPs possess excellent photothermal and photodynamic therapy (PTT/PDT) performance, which is adequate to destroy tumor cells by physical and chemical attack. Especially, these TA-Fe/ [email protected] NPs are capability of promoting the dendritic cells (DCs) maturation and antigen presentation via manganese-mediated cGAS-STING pathway activation, finally activating cytotoxicity T lymphocyte and promoting memory T lymphocyte differentiation in the peripheral lymphoid organs. In conclusion, this research offers a versatile metal-polyphenol nanoplatform to integrate functional metals and therapeutic molecule for topical phototherapy and robust anti-tumor immune activation.
研究领域:
生物医学工程
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免疫学
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肿瘤学
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Jianqiu Yang,Zhenyu Chen,Tao Zhang,Rongxiang Hu,Dingguo Wang,Shiwei Chen,Lingxian Zhang,YunFeng Ge,Yongbing Wu
Hybrid macrophage/cardiomyocyte membrane coating achieves immune evasion and myocardial targeting. • Pomelo peel cellulose-based microneedles enable 14-day sustained release of ginsenoside Rg1. • The system blocks the mtDNA-cGAS-STING inflammatory axis by preserving mitochondrial integrity. • Treatment promotes M2 macrophage polarization and angiogenesis in infarcted myocardium. • CM@PPG-MNs significantly improve survival and cardiac function in rat myocardial infarction. Myocardial infarction (MI) leads to severe inflammatory reaction and mitochondrial damage, which will inevitably lead to heart failure. There are many problems in the application of traditional nano-carriers, especially the facts that they are easily cleared quickly by the immune system, have poor heart targeting and release drugs too fast. In order to overcome the above problems, a hybrid cell membrane targeted delivery system was designed in this study. In this system, macrophage membrane and myocardial cell membrane were fused, and ginsenoside Rg1 was encapsulated, and then the complex was loaded into a natural pomelo peel cellulose hydrogel microneedle patch to form CM@PPG-MNs. The macrophage membrane component in the carrier can help it escape from immune system attack, while the myocardial cell membrane component can accurately target the damaged myocardial tissue. The microneedle patch can penetrate the surface of the heart and realise the controlled release of ginsenoside Rg1 within the critical 14-day treatment cycle. Studies have confirmed that the system can stop the vicious cycle of inflammation and mitochondrial damage by blocking the mtDNA-cGAS-STING pathway, and at the same time promote the polarization of macrophages from pro-inflammatory M1 type to repair-oriented M2 phenotype. In the rat model of myocardial infarction, the treatment of CM@PPG-MNs patch significantly improved the survival rate of the model animals and reduced the mortality rate from 54.17% to 16.67%. The natural microneedle system developed in this study has excellent efficacy and high application potential in the field of myocardial repair. Schematic illustration of the synthesis, in vivo delivery, and intracellular mechanisms of the macrophage membrane-camouflaged biomimetic microneedle patch (CMV-RG1 Bio-MN Patch) for myocardial infarction treatment, detailing the extraction of cellulose nanofibers and RAW 264.7 macrophage membranes to fabricate a microneedle patch loaded with Rg1 encapsulated nanovesicles (Rg1@CM), which, upon implantation onto the infarcted area, utilizes homologous “self” recognition to evade host macrophage attack and specifically target injured cardiomyocytes, where Rg1 exhibits a dual-pathway blockade by inhibiting the mtDNA-triggered cGAS-STING inflammatory pathway (downregulating IL-1β, IL-6, TNF-a and upregulating IL-4, IL-10) and preventing mitochondrial Cytochrome c release to mitigate ATP depletion, synergistically promoting ROS scavenging, angiogenesis, and M2 macrophage polarization. Download: Download high-res image (200KB) Download: Download full-size image
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Shousheng Liu,Haiping Zhang,Ronghuan Du,Xi Gao,Tianren Wang,Wenping Qin,Dan Sun,Hui Liang,Peng Wang
Emerging research evidence has established the critical role of inflammatory cascades in the development and progression of alcoholic liver injury with hepatocellular death serving as a principal driver. Notably, the dysregulated interplay between mitochondrial homeostasis and pyroptosis is primarily responsible for the alcohol-induced aberrant liver immune microenvironment, characterized by nonresolving inflammation. Given the considerable limitations in the current treatment for alcoholic steatohepatitis (ASH), it is imperative to explore targeted nutritional interventions as alternative therapies. Here, we established an ASH model with C57BL/6J mice and demonstrated that astaxanthin (AST) administration significantly protected against alcohol-induced inflammatory liver injury through dual mechanisms: 1) suppression of hepatocyte pyroptosis by inhibiting the NLRP-3/Caspase/GSDMD signaling axis and 2) mitigation of mitochondrial dysfunction evidenced by structural membrane integrity restoration and redox homeostasis rebalancing. Mechanistically, AST intervention impeded the cytoplasmic translocation of mitochondrial DNA (mtDNA), thereby concurrently inhibiting AIM2 inflammasome activation and cGAS/STING signaling. In vitro studies further confirmed dose-dependent attenuation of alcohol-induced hepatotoxicity by AST, marked by reduced pyroptotic cell death and diminished proinflammatory cytokine secretion (IL-1β, IL-18). Mitochondrial protection was further evidenced through restored membrane potential (ΔΨm), decreased cytoplasmic Cytochrome C release, and attenuated mtDNA leakage. Moreover, we identified a novel molecular interaction, wherein AST competitively binds lipid-binding motifs within the β1−β2 loop of the GSDMD-N-terminal domain, potentially interfering with pyroptotic pore formation. Further overexpression experiments confirmed the improvement effect of AST on pyroptosis induced by GSDMD-N pore formation. Concurrently, AST exhibited potent antioxidant effects against alcohol-induced cardiolipin peroxidation, suggesting dual therapeutic modalities targeting both pyroptotic execution and mitochondrial membrane stabilization. Collectively, our findings identify AST as a promising candidate for therapeutic interventions against alcoholic inflammatory liver injury through coordinated modulation of the pyroptosis-mitochondrial homeostasis crosstalk, offering novel insights into nutritional intervention strategies for alcohol-related liver pathologies.
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高影响因子
Journal of Translational Medicine
·
2026
·Vol. 24
·期 1
·539
·
IF 9.7
Gao Yuan-Yuan,Sun Wen-Shuang,Sun Zi-Ying,Wang Jun-Rui,Lv Zhong-Yang,Li Yu-Jia,Tian Hao-Yuan,Bao Zheng-Yang,Qiu Xin-Ran,Wang Zheng,Zheng Shi-Zhong,Shao Jiang-Juan,Zhang Zi-Li,Meng Jia
Background Tendinopathy is a prevalent orthopaedic condition characterized by disrupted tendon homeostasis, with oxidative stress being a key contributing mechanism. Although the natural compound 18-β-Glycyrrhetinic acid (GA) exhibits antioxidant properties and is a therapeutic candidate for tendinopathy, its precise molecular mechanism remains unclear. This study aimed to elucidate how GA alleviates tendinopathy, with a focus on its role in regulating the HMGB1-cGAS-STING axis and NLRP3 inflammasome activation in the context of oxidative stress. Methods We employed single-cell RNA sequencing (scRNA-seq) of clinical samples, proteomics of animal tissues, and comprehensive pharmacological assays to investigate the mechanisms of tendinopathy. Furthermore, the rat tendinopathy model and H 2 O 2 -induced oxidative stress model of tendon stem cells (TSCs) were used to validate the protective effects of GA. Results We found that GA significantly reduced oxidative stress and subsequent inflammation, thereby mitigating collagen disruption in rats with tendinopathy. Notably, scRNA-seq revealed that the proportion of TSCs increased significantly during tendinopathy, which were particularly susceptible to reactive oxygen species (ROS). TSCs from oxidative damage and inhibited activation of the NLRP3 inflammasome by suppressing the cGAS-STING pathway. Mechanistically, GA promoted cGAS degradation by enhancing its interaction with the mitochondrial E3 ubiquitin ligase Mul1. This effect was mediated through high-mobility group box 1 (HMGB1), as GA disrupted the HMGB1-cGAS interaction. Specifically, GA induced methylation of HMGB1 at lysine 43, a modification essential for its activity. This methylation was catalyzed by the methyltransferase DOT1L, which was upregulated and directly bound by GA. Collectively, GA alleviates tendinopathy by targeting the DOT1L-HMGB1-cGAS axis to resolve oxidative stress and inflammation. Conclusion Collectively, our findings provide new insights into how oxidative stress accelerates tendinopathy progression. Moreover, they delineate the mechanism by which GA in mitigates oxidative damage and inflammation in TSCs by inhibiting the co-localization of HMGB1 and cGAS. Overall, this study offers scientific support for further developing GA as a promising therapeutic agent for tendinopathy treatment. Graphical The alternative text for this image may have been generated using AI.
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Bioactive Materials
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2026
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IF 23.6
Ning Huang,Lingyan Cao,Yue Xu,Lisha Pan,Ao Zheng,Xiao Wang,Xinquan Jiang
Prolonged periodontal inflammation and progressive alveolar bone loss are typical manifestations of periodontitis. Antioxidative therapies targeting the central role of reactive oxygen species (ROS) have been explored, but lack of subcellular specificity limits efficacy. Mitochondria function as an upstream redox hub that drives oxidative stress, inflammatory responses, and alveolar bone resorption, making mitochondrial redox modulation a promising yet underexplored strategy for periodontitis therapy. Herein, we developed a mitochondria-targeted, redox-responsive nanocomposite (TC/pSeSe) that enables programmable redox modulation of the pathological periodontal microenvironment. The antioxidative core consists of a ROS-responsive diselenide-containing copolymer (pSeSe) capable of selenium release, while the triphenylphosphine/chitosan (TC) coating confers mitochondrial-targeted, controlled redox activity, mucosal retention and cationic antibacterial properties. With preferential mitochondrial localization, TC/pSeSe undergoes diselenide bond cleavage and selenium release under oxidative stress, thereby restoring mitochondrial redox homeostasis and attenuating downstream mitochondrial DNA (mtDNA)-cGAS-STING-mediated inflammatory signaling. Through combined ROS scavenging and selenium-mediated support, TC/pSeSe mitigates ferroptosis in a partially glutathione peroxidase 4 (GPX4)-dependent manner and restores osteogenic potential in bone marrow-derived stem cells. In parallel, TC/pSeSe exhibits antibacterial activity against periodontal pathogens through combined selenium and the cationic TC coating functionalities. In vivo , TC/pSeSe restored alveolar bone regeneration and attenuated periodontal inflammation. Collectively, this study proposes a mitochondria-centered redox modulation strategy, providing a comprehensive and promising therapeutic approach for periodontitis treatment.
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高影响因子
Acta Biomaterialia
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2026
·
IF 9.6
Renyuan Liu,Yubo Tan,Yuli Jiang,Jingwen Zheng,Wenjie Ni,Sheng Lin,Jing Lin,Dandan Chen,Pengfei Lyu,Yaohui He,Gang Liu,Zhixiang Lu
The escalating challenge of chemoresistance in breast cancer treatment severely limits clinical efficacy, necessitating the urgent development of innovative strategies that synergistically enhance tumor cell eradication and remodel the anti-tumor immune microenvironment. To address this, we developed a D-A structured theranostic probe, 1HA4CD, featuring a dihydroxanthene-fluorophore with diethylamino donor and acrylonitrile/pyridyl acceptors. Upon laser irradiation, 1HA4CD enables spatiotemporally controlled reactive oxygen species (ROS, primarily singlet oxygen, 1 O₂) generation. Crucially, its precise nuclear localization facilitates the induction of high-concentration ROS within the nucleus, causing irreversible oxidative genomic DNA damage. RNA sequencing analysis revealed that the transient nuclear ROS overload not only directly induces DNA double-strand breaks (DSBs) but also inhibits DNA repair pathways, creating a "dual-hit" effect that effectively overcomes the chemoresistance associated with traditional DNA-damaging agents through a nuclear-targeted photodynamic mechanism. DNA fragments released into the cytoplasm post-damage are recognized by the cytosolic DNA sensing machinery, subsequently activating the cGAS-STING signaling cascade, which leads to the systemic activation of both innate and adaptive immune responses. In vivo animal studies demonstrated that 1HA4CD-mediated photodynamic therapy exhibits significant therapeutic efficacy against breast cancer, coupled with a favorable biosafety profile. This research presents a nuclear-targeted molecular tool for photodynamic immune activation therapy and advances the development of combination therapies based on DNA damage-induced immune responses. Statement of Significance Photodynamic therapy (PDT) often suffers from limited efficacy due to insufficient subcellular targeting and the inability to induce systemic anti-tumor immunity, especially in chemoresistant cancers. This work presents 1HA4CD, a nuclear-targeting probe designed to enhance PDT by generating spatiotemporally controlled ROS directly within the nucleus. This approach causes direct DNA double-strand breaks while concurrently inhibiting DNA repair, and further activates the cGAS-STING pathway via damaged nuclear DNA fragments, thereby bridging localized photodamage with systemic immune activation. The resulting “dual-hit” mechanism effectively addresses chemoresistance in breast cancer. By integrating precise subcellular targeting with immunomodulation, this study provides a rational strategy for developing bioactive materials that combine PDT with immunotherap.
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高影响因子
Theranostics
·
2026
·Vol. 16
·期 4
·1701
·
IF 13.3
Shan Meng,Jinfeng Duan,Jikai Zhao,Zijun Zhou,Boxuan Sun,Yinli Xu,Tao Huang,Tao Hong,Xin Chen,Tong Su,Liming Yu,Huishan Wang
Aims: Type 2 diabetes mellitus (T2DM) significantly elevates the likelihood of atrial fibrillation (AF); However, the precise mechanisms remain incompletely elucidated. Mitochondrial dysfunction is a hallmark of diabetic cardiomyopathy, and recent evidence suggests that activation of the cGAS-STING signaling pathway may contribute to metabolic inflammation in the atria. This study aims to investigate the role of mitochondrial DNA (mtDNA)-mediated cGAS-STING activation in promoting diabetes-associated atrial fibrillation (AF) through cardiomyocyte-macrophage crosstalk. Methods and results: Using a high-fat diet combined with streptozotocin through intraperitoneal injection, we induced a diabetic mouse model. We observed increased AF inducibility, oxidative stress, and mitochondrial ultrastructural abnormalities, along with elevated expression of STING pathway components and pro-inflammatory cytokines in atrial tissue. RNA sequencing and histological analyses confirmed dysregulation of mitochondrial quality control (MQC), including impaired mitophagy, imbalance in fusion and fission, and reduced mitochondrial biogenesis. In vitro , HL-1 atrial cardiomyocytes exposed to high glucose and palmitic acid showed excessive production of mtROS and cytosolic release of mitochondrial DNA (mtDNA), which in turn triggered cGAS-STING activation. A transwell co-culture system revealed that cardiomyocyte-derived mtDNA was engulfed by RAW 264.7 macrophages, promoting M1 polarization of macrophages and further amplifying inflammatory signaling. Importantly, pharmacological intervention with the mitochondrial antioxidant mito-TEMPO or cardiomyocyte-specific STING knockdown suppressed inflammatory responses, reversed atrial remodeling, and reduced AF susceptibility. Notably, STING overexpression sustained inflammatory pathways independently of suppressing oxidative stress, highlighting cGAS-STING signaling as a downstream effector of mitochondrial damage. Conclusion: Impairment of mitochondrial quality control promotes atrial inflammation and remodeling in diabetes through mtDNA-induced cGAS-STING activation and cardiomyocyte-macrophage communication. Targeting this pathway may offer a novel strategy for AF management in metabolically compromised hearts.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
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IF 5.9
Nan Wang,Shiyu Ma,Fangyu Jiao,Zhe Yu,Fengshu Fei,Jianting Huang,Chuanlong Guo
RL/BAI nanomicelles (~100 nm) enhance baicalein biocompatibility. • RL/BAI triggers mitochondrial dysfunction and mtDNA release in TNBC cells. • RL/BAI activates cGAS-STING pathway to suppress tumor growth and metastasis. Triple-negative breast cancer (TNBC) remains an intractable malignancy due to the lack of specific therapeutic targets and high metastatic potential. Herein, we fabricated rhamnolipid (RL)-encapsulated baicalein (BAI) nanomicelles (RL/BAI) via a thin-film hydration method. Molecular dynamics (MD) simulations revealed that RL and BAI spontaneously assembled into stable nanomicelles (~100 nm) driven by van der Waals and hydrophobic interactions, achieving high encapsulation efficiency (~85 %) and excellent biocompatibility. In 4T1 cells, RL/BAI nanomicelles enhanced cellular uptake and achieved efficient mitochondrial colocalization, triggering mitochondrial membrane potential (MMP) collapse, excessive mitochondrial reactive oxygen species (mtROS) generation, and mitochondrial DNA (mtDNA) release. These events activated the cGAS-STING pathway, as evidenced by increased phosphorylation of STING, TBK1, and IRF-3, together with upregulation of IFN-γ and NF-κB, ultimately promoting immunogenic cell death. In 4T1 xenograft models, RL/BAI significantly inhibited primary tumor growth and lung metastasis, remodeled the pro-inflammatory tumor microenvironment by upregulating pro-inflammatory cytokines and promoting dendritic cell maturation, with no obvious systemic toxicity. Collectively, RL/BAI nanomicelles exert anti-TNBC effects through mitochondrial damage and cGAS-STING pathway activation, providing a novel natural biosurfactant-based nanomedicine strategy for TNBC treatment.
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高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Yifan Guo,Taiqi Xue,Xiangfei Meng,Pu Yan,Meng Zhang,Qian Zhang,Tongxia Li,Kaifeng Shi,Ning Zhang
Background The cGAS/STING-mediated inflammatory response plays a key role in diabetic kidney disease (DKD) pathogenesis. However, effective anti-inflammatory therapies to halt disease its progression remain unavailable. The Qihuang Yishen (QHYS) formula has been demonstrated to reduce proteinuria and halt the course of DKD. However, the underlying mechanism of QHYS remains unclear. Purpose The purpose of this study was to determine whether QHYS had anti-inflammatory effects on DKD by targeting the cGAS/STING pathway both in vitro and in vivo . Methods In vivo , DKD models were established in KK-Ay mice using a high-fat diet. In vitro , human renal tubular epithelial cells (HK-2) were exposed to high glucose (HG) and palmitic acid (PA) for 24 hours to simulate renal tubular injury. Both experimental settings received interventions with QHYS or canagliflozin (positive control drug). Bioactive components in QHYS-containing serum were characterized by HPLC-ESI/MS. Body weight, random blood glucose, renal function markers, urinary protein levels, renal tubular injury indicators, and renal histological lesions were evaluated. Mitochondrial ultrastructure was analyzed by transmission electron microscopy (TEM). Western blotting quantified mitochondrial proteins TFAM and TOM20. Cell viability was assessed via CCK-8 assay, while ELISA kits measured IL-6 and TNF-α levels in cell supernatant. Quantitative PCR assessed expression of mtDNA and inflammatory mediators (IL-6, TNF-α, IFN-γ and CXCL10 mRNA). For cGAS/STING pathway analysis, key proteins were evaluated through western blotting, immunofluorescence, and immunohistochemistry. Additionally, mtDNA transfection experiments in HK-2 cells elucidated QHYS's regulatory mechanism on this pathway. Results HPLC-ESI/MS identified 32 principal bioactive components in QHYS. In vivo experiments showed that QHYS significantly reduced Scr and UREA levels ( P < 0.05), decreased UACR, 24 h UTP and renal tubular injury markers NAG and NGAL levels ( P < 0.01), and alleviated renal histopathological damage in KK-Ay mice, including glomerular hypertrophy, mesangial matrix expansion, tubular vacuolar degeneration, and tubulointerstitial inflammation. Moreover, QHYS ameliorated mitochondrial structural damage, upregulated the expression of TFAM and TOM20 ( P < 0.05), and suppressed cGAS/STING pathway activation ( P < 0.01). In vitro experiments demonstrated that QHYS alleviated mitochondrial damage ( P < 0.05) and mtDNA leakage ( P < 0.01), and inhibited cGAS/STING signaling and downstream inflammation ( P < 0.05). More importantly, transfecting mtDNA into the cytoplasm to mimic the leakage process demonstrated that QHYS-containing serum directly inhibits cGAS/STING pathway activation ( P < 0.05), and this mechanism also alleviated renal tubular injury in DKD. Conclusion QHYS attenuates renal tubular inflammatory damage via cGAS/STING pathway regulation. This pioneering study provides the first evidence that herbal medicine exerts renal tubule protection through multi-target regulation of innate immune-mediated inflammatory injury in metabolic nephropathy, offering novel scientific evidence for DKD intervention.
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