Frontiers in Immunology
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2026
·
IF 5.9
Qingyu Zhang,Kailun He,Mohd Shafiq Aazmi,Mohd Fakharul Zaman Raja Yahya
Background: Extracellular vesicles (EVs) of probiotics are an important pathway for probiotics to exert probiotic effects. EVs of Clostridium butyricum (C. butyricum) has great potential in immunotherapy. The aim of this study is to investigate the regulatory effect of C. butyricum EVs on the pyroptosis-related gene network in LPS-stimulated macrophages and explore its potential molecular mechanisms.Methods: Differential centrifugation was used to isolate C. butyricum EVs, and EVs were characterized by transmission electron microscopy, NTA, and ZETA potential. PI staining was employed to confirm the stimulatory effect of LPS on RAW264.7 cells. Transcriptome sequencing and qPCR were performed to validate the regulatory effects of EVs on pyroptosis-related genes (PRGs) in LPS-stimulated RAW264.7 cells.Results: C. butyricum EVs exhibited a bilayer membrane structure with a median particle size of 144.4 ± 85.7 nm and a ZETA potential of -37.56 ± 1.08 mV. PI staining showed that LPS induced cell death in RAW264.7 macrophages, while EV treatment significantly affected the expression of pyroptosis-related genes IL-18 and IL-33 (q < 0.05). Transcriptome analysis revealed that C. butyricum EVs induce inflammation and cytokine secretion in RAW264.7 macrophages through the JAK-STAT signaling pathway and Cytokine receptor interaction. EVs pretreatment (10/20 μg/mL) regulated the expression of 14 PRGs in a concentration-related manner, including significant upregulation of IL-6 and P2rx7 (q < 0.01) and inhibition of ZBP1 and Tnf (q < 0.05). The gene interaction network showed a positive correlation (r=0.82) between IL-6 and P2rx7, and a negative correlation (r=-0.75) between ZBP1 and P2rx7.Conclusion: C. butyricum EVs remodel the pyroptosis-related regulatory network by modulating key genes such as IL-6, P2rx7, and ZBP1, suggesting their potential role in fine-tuning LPS-induced inflammatory responses in macrophages.
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BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Hao Wang,Chunliu Li,Xiao Wang,Feng Yan,Bihan Li,Jiahui Gao,Kuo Zhang,Jiahong Wang
Diabetic kidney disease (DKD), a predominant microvascular complication of diabetes mellitus, still lacks curative therapies to completely halt its progressive deterioration. Our study investigated the renoprotective mechanisms of dapagliflozin (dapa) in DKD. Through bioinformatic analysis of clinical DKD datasets, preclinical in vivo and in vitro assays, we identified absent in melanoma 2 (AIM2) as a critical pyroptosis-associated gene upregulated in DKD. In silico structure-based validation revealed that dapa stably binds to the catalytic domain of silent information regulator 1 (SIRT1) via key residues GLN-361 and SER-365, suggesting its potential to modulate SIRT1 deacetylase function. Gain- and loss-of-function assays confirmed that SIRT1 is the core functional target of dapa: dapa upregulated SIRT1 protein expression to inhibit nuclear factor-κB (NF-κB) signaling, thereby blocking AIM2 inflammasome-mediated renal tubular pyroptosis and oxidative damage. These findings reveal a previously unreported mechanism by which dapa regulates SIRT1/NF-κB/AIM2 signaling to exert renoprotection, and provide promising therapeutic targets for the clinical management of DKD.
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Advanced Healthcare Materials
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2026
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IF 11
Yangyang Lu,Yan Li,Hongyang Yan,Xueying Sun,Xin Li,Yuanyuan Fang,Siyi Zhang,Jingwen Tian,Xin Wang,Cheng Luo,Wensheng Qiu,Weiwei Qi
Neutrophils combat tumors through a distinct enzymatic cascade involving superoxide dismutase (SOD) and myeloperoxidase (MPO), a biocatalytic mechanism that offers a promising platform for novel antitumor strategies. However, the clinical translation of natural enzymes is hindered by inherent limitations, including poor stability and high immunogenicity. In this context, nanozymes have emerged as advanced tools for tumor therapy, with the development of cascade catalytic nanosystems representing a major research frontier. This study designed multifunctional copper-caffeic acid metal-phenolic networks (Cu-CA MPNs). Upon lysosomal entry, the nanozyme mimics the neutrophil's SOD-MPO cascade to continuously generate substantial reactive oxygen species (ROS), notably hypochlorous acid (HOCl). This process directly damages lysosomes, promotes mitochondrial ROS accumulation, and upregulates the expression of GSDMD-N and GSDME-N, ultimately triggering pyroptosis. Simultaneously, Cu-CA MPNs released from ruptured lysosomes cause abnormal copper ion accumulation within mitochondria. This enhances oligomerization of the DLAT protein and downregulates key metabolic proteins-including ACO2, ETFDH, LIAS, and FDX1-thereby inducing cuproptosis. In a tumor-bearing mouse model, Cu-CA MPNs demonstrated potent antitumor efficacy and favorable biosafety. This work provides a new perspective for tumor catalytic therapy using nanozymes that simulate the neutrophil enzymatic cascade.
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Nutrients
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2026
·Vol. 18
·期 13
·2071
·
IF 5.8
Jian-Qiang Wang,Bing-Bing Hu,Yi-Yue Wang,Ya-Wei Lu,Xiao-Jie Gong,Shan Tang,Ling-Jie Song,Yin-Shi Sun,Jing-Tian Zhang,Zi Wang,Wei Li
Objectives:Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation.Methods:In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism.Results:Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner.Conclusions:Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine.
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Advanced Science
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2026
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IF 14.1
Yang Hong,Haitao Wu,Weitao Wang,Xuan Zhang,Qian Chen,Yaoyu Hu,Zhengbao Zha
Cellular pyroptosis, a pro‐inflammatory form of programmed cell death, emerges as a promising strategy for cancer immunotherapy. However, gene methylation hampers the expression of gasdermin E (GSDME), a pivotal protein in the caspase‐3‐mediated pyroptosis pathway, across numerous malignancies, including triple‐negative breast cancer (TNBC). This study elucidated that a colloidal hydrogel (GDLC hydrogel) loaded with decitabine (DAC) and crosslinked with lanthanum carbonate nanosheets (LCNSs) and gelatin nanoparticles (Gela NPs) could instigate pyroptosis in TNBC cells, specifically 4T1 cells. Within the tumor microenvironment (TME), the synergistic interaction between DAC and La 3+ reversed the epigenetic silencing of the GSDME gene, while concurrently activating caspase‐3, thus facilitating pyroptosis induction. Although monotherapy with La 3+ ‐induced apoptosis proved insufficient in tumor suppression, the concurrent inhibition of methyltransferase via DAC markedly suppressed both primary and recurrent tumors. Moreover, the combinatory application of the GDLC hydrogel and immune checkpoint inhibitors effectively neutralized the immunosuppressive TME of TNBC, triggered an anti‐tumor immune response and engendered a sustained immune memory effect. This strategy significantly curtailed tumor recurrence and metastasis, consequently improving the survival rates of mice in the 4T1 tumor‐bearing mouse model. In conclusion, this colloidal hydrogel platform introduced an innovative paradigm for the immunotherapy of triple‐negative breast cancer. The Gela/decitabine/La 2 (CO 3 ) 3 colloidal (GDLC) hydrogel developed here could reverse the epigenetic silencing of the GSDME gene by the synergistic interaction between DAC and La 3+ , while concurrently activating caspase‐3, thus facilitating pyroptosis induction under the tumor microenvironment. Moreover, the combinatory application of the GDLC hydrogel and immune checkpoint inhibitors effectively triggered robust anti‐tumor innate & adaptive immune responses and engendered a sustained immune memory effect.
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Nature Communications
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2026
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IF 18.1
Zhiyun Wang,Ziwei Chen,Sheng Wang,Luna Cui,Minghao Tang,Xianhua Liu,Tao Wang,Xueping Li
Microplastics (MPs), ubiquitous environmental pollutants, can enter the human body and exacerbate health risks. Polyvinyl chloride MPs (PVC-MPs) are emerging contaminants of particular concern due to direct clinical exposure pathway. However, the role of PVC-MPs in pathogenic bacterial infections remains poorly understood. Here, we investigate the role of PVC-MPs for the pathogenicity of uropathogenic Escherichia coli (UPEC), the primary causative agent of urinary tract infections (UTIs). Results demonstrate that PVC-MPs significantly enhance both acute and chronic UTIs. Mechanically, PVC-MPs act as carriers, enriching UPEC on their surface and enhancing UPEC invasion of bladder epithelial cells (BECs) via receptor-independent pathway, thereby promoting UPEC colonization in mouse bladders and kidneys. After entering BECs, intracellular PVC-MPs induce mitochondrial dysfunction, causing mitochondrial reactive oxygen species accumulation and mitochondrial DNA leakage, which activate Caspase-1-dependent pyroptosis, promoting urothelial cell shedding and UPEC chronic infection. These findings establish PVC-MPs as mediators of UTI pathogenesis, providing critical mechanistic insights into how environmental pollutant exposure may enhance susceptibility to infectious diseases. Polyvinyl chloride microplastics have been detected within clinical settings and may influence bacterial infections. Here, the authors demonstrate that these microplastics facilitate acute infection by uropathogenic E. coli, helping the bacteria evade immune cells and increase shedding.
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2026
·Vol. 45
·期 1
·75
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IF 14.3
Ren Ting,Chen Xue,Wang Xiaozhen,Xu Yantian,Shao Na
Background The aggressive cancer known as pancreatic ductal adenocarcinoma (PDAC) has a remarkably poor response to treatment, especially gemcitabine (GEM). As a member of the noncanonical IκB kinase family, inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) is known to regulate tumor progression in multiple cancer types. However, its functional role in modulating chemosensitivity and its impact on cell death pathways in PDAC remain unclear. Materials and methods We examined IKBKE expression in patient tumor tissues and publicly available databases and assessed its prognostic value to investigate its function in PDAC chemoresistance. Loss-of-function approaches, including shRNA knockdown and pharmacological inhibition using amlexanox, were employed in vivo and in vitro. Furthermore, cytotoxicity along with cell death patterns induced by GEM were assessed through flow cytometry, electron microscopy, and CCK-8 assays. Co-IP and GST pull-down assays were applied to determine whether IKBKE interacts with gasdermin E (GSDME), the executioner protein of pyroptosis. Moreover, in vitro kinase assays, phosphorylation mass spectrometry, and site-specific gain-/loss-of-function mutant functional experiments were conducted to investigate the specific pathways via which IKBKE affects GSDME-mediated pyroptosis. The therapeutic potential of IKBKE targeting was further validated using patient-derived tumor organoids and xenograft models. Results IKBKE was significantly elevated in PDAC tissues and was closely linked to worse clinical outcomes. Functional studies of the signaling pathway showed that via the activation of the protein kinase B/glycogen synthase kinase-3β signaling pathway, IKBKE facilitates the aggressive phenotype of PDAC cells. IKBKE inhibition or silencing increased GEM sensitivity and caused caspase-3/GSDME-dependent pyroptosis in PDAC cells. Co-IP and GST pull-down analysis revealed IKBKE–GSDME interaction. Further in vitro cleavage and kinase assays, mass spectrometry analysis, and mutant functional studies showed that IKBKE inhibits pyroptosis by phosphorylating GSDME at Thr6, thereby hindering its cleavage by caspase-3. Treatment with amlexanox markedly suppressed tumor growth and synergized with GEM to enhance anti-tumor efficacy in organoid models by targeting IKBKE. Conclusion Our findings identify IKBKE as a key regulator of chemotherapy-induced pyroptosis in PDAC. Specifically, IKBKE phosphorylates GSDME at Thr6, which alters its conformation, thereby impeding caspase-3–mediated cleavage, ultimately contributing to GEM chemoresistance. IKBKE targeting reverses GEM resistance and enhances tumor immunogenic cell death via the caspase-3/GSDME pathway, supporting IKBKE inhibition as a promising therapeutic strategy for PDAC. Graphical The alternative text for this image may have been generated using AI.
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JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Chang Peng,Bing Han,Qiao Qu,Aiyang Tong,Siqi Wang,Ji Li,Dalu Wang,Yang Ge
Pyroptosis-induced production of inflammatory cytokines and elevated levels of cell-free DNA (cfDNA) are major pathogenic drivers of intestinal inflammatory diseases. Inflammatory macrophages perform a vital role in mediating inflammatory immune responses, and their targeted modulation represents a promising therapeutic strategy for colitis. Cationic nanoparticles possess considerable therapeutic promise in inflammatory disorders due to their high affinity for cfDNA. In this work, we established a combinatorial therapeutic strategy using reactive oxygen species (ROS)-responsive cationic nanoparticles that simultaneously scavenge cfDNA and transport 4-octyl itaconate (4-OI), a potent agent against pyroptosis. This dual-functional nanosystem effectively rebalances the inflammatory microenvironment by suppressing pyroptosis and neutralizing cfDNA in colonic tissues. The nanoparticles exhibited excellent biocompatibility and robust therapeutic efficacy in the context of experimental IBD in mice, with sustained drug release triggered by ROS overexpression in inflamed regions. Notably, this approach demonstrates minimal cytotoxicity and leads to substantial amelioration of disease pathology, offering an innovative therapeutic approach for the targeted control of inflammatory diseases through the coordinated targeting of multiple pathological axes.
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ANALYTICAL CHEMISTRY
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2026
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IF 7.3
Xueqi Han,Wenting Guo,Yong Wang,Lin Liu,Mengmeng Lv,Jing Li,Jiangtao Ren,Yongdong Jin,Erkang Wang
Zinc is a common redox element and plays a vital role in immune response, catalysis, structure, and signal regulation. Tracing intracellular Zn2+ dynamics is, therefore, crucial for understanding physiological processes. Since a glass nanopipette is a good sensing platform for single-cell detection with little damage to the cell membrane, in this study, we developed DNAzyme-functionalized glass nanopipettes (D-GNs) for single-cell Zn2+ detection based on the catalytic activity of Zn2+-dependent DNAzymes. In the presence of Zn2+, DNAzyme-modified gold nanoparticles (D-AuNPs) were released from the inner wall of the nanopipette, leading to a change in ionic current rectification. D-GNs exhibited good sensing performance in vitro and can be applied to effectively detect Zn2+ in HeLa cells under electrical stimulation. This functional nanopipette-based platform offers a new strategy for probing intracellular ion variations and evaluating the physiological state of individual cells.
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CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Hongyu Yang,Yuelin Zhao,Sen Mu,Siqi Wang,Aiyang Tong,Dongkai Wang,Jiajia Jia,Ji Li
HA@CZ enables acid-responsive local Ca 2+ /Zn 2+ ion therapy. • Zn 2+ impairs Ca 2+ extrusion and drives sustained Ca 2+ overload. • Dual-ion stress induces caspase-1/GSDMD and caspase-3/GSDME pyroptosis. • HA@CZ cascade-induces pyroptosis and activates the STING pathway. • Local HA@CZ treatment sensitizes 4 T1 tumors to PD-1 blockade. Triple-negative breast cancer responds poorly to immune checkpoint blockade, partly because of insufficient tumor-local immune priming. Controlled delivery of bioactive ions offers an opportunity to induce inflammatory tumor cell death while limiting nonspecific systemic exposure. Here, we developed hyaluronic acid-modified, zinc containing calcium carbonate nanoparticles (HA@CZ) for acid-responsive synchronized Ca 2+ /Zn 2+ delivery. HA@CZ remained colloidally stable under physiological conditions but released Ca 2+ and Zn 2+ more rapidly under tumor relevant acidic conditions. HA@CZ markedly promoted intracellular Ca 2+ /Zn 2+ accumulation, induced mitochondrial dysfunction, and triggered gasdermin dependent pyroptosis through the caspase-1/GSDMD and caspase-3/GSDME axes. Mechanistically, the key distinction of HA@CZ does not lie in Ca 2+ overload alone, but in converting Ca 2+ overload from a direct ion burden process into a Zn 2+ initiated Ca 2+ homeostasis collapse mechanism. Zn 2+ impaired mitochondrial energy metabolism and ATP dependent Ca 2+ extrusion, thereby lowering the threshold for sustained Ca 2+ overload after synchronized ion release. The resulting dual ion stress promoted mitochondrial deoxyribonucleic acid leakage and activated cyclic GMP–AMP synthase stimulator of interferon genes signaling, thereby coupling tumor cell pyroptosis with endogenous deoxyribonucleic acid sensing activation. In syngeneic 4 T1 tumor models, HA@CZ suppressed tumor growth after both systemic and local administration, promoted dendritic cell maturation and CD8 + T-cell infiltration, and remodeled the tumor immune microenvironment toward a pro-inflammatory phenotype. Intratumoral studies confirmed its intrinsic therapeutic superiority over free CaCO₃, Zn 2+ , and their physical mixture, while combination with anti-PD-1 therapy enhanced control of both primary and distant tumors. Furthermore, tumor re-challenge experiments demonstrated that HA@CZ induced durable antitumor immune memory. These findings establish HA@CZ as a controlled-release ion nanotherapeutic that couples synchronized Ca 2+ and Zn 2+ delivery to pyroptosis associated immune activation and checkpoint blockade sensitization. Download: Download high-res image (150KB) Download: Download full-size image
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Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-11
·
IF 7
Mao Jianyu,Lu Jiajia,Wang Sheng,Jiang Xin,Li Jing,Fu Qiang,Lu Nan,Zhu Lei,Chen Aimin,Ma Jun
Pyroptosis, a form of lytic and inflammatory programmed cell death mediated by gasdermin proteins, contributes to progressive spinal cord neurodegeneration following neural trauma. Nevertheless, the regulatory mechanisms governing this process remain inadequately characterized. In this investigation, hydrogen sulfide (H₂S) was identified as an endogenous inhibitor of neuronal pyroptosis, functioning through Rac1-dependent NLRP3 inflammasome signaling. In a rat model of lumbosacral plexus nerve injury, H₂S treatment significantly decreased pyroptosis-associated markers (NLRP3, caspase-1, GSDMD) and enhanced neuronal survival. In vitro, the administration of H₂S effectively mitigated hypoxia-induced neuronal pyroptosis by inhibiting the assembly of the NLRP3 inflammasome. Mechanistically, our findings indicate that H₂S selectively persulfidates Rac1, inhibiting its GTPase activity and reducing reactive oxygen species (ROS) production, both of which are critical for inflammasome priming. Molecular dynamics simulations and site-directed mutagenesis further confirmed that H₂S persulfidation of Rac1 at Cys178 alters its conformation, thereby suppressing NLRP3 inflammasome activation. Taken together, our findings reveal a novel post-translational regulatory mechanism by which H₂S mitigates pyroptotic neuronal death through Rac1 persulfidation, highlighting the H₂S-Rac1 axis as a promising therapeutic target for neuroprotection in pyroptosis-related neurodegeneration.
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Scientific Reports
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2025
·Vol. 15
·期 1
·1-11
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IF 3.9
Xu Guobin,Wang Junlong,Gu Na,Yang Tiansong
Pyroptosis is a pathogenenic mechanism of polycystic ovary syndrome (PCOS). N5-methylcytosine (m5C) methylation is a RNA modification that affects the progression of diseases. However, its role in PCOS remains not understood. This study aimed to investigate the role of NSUN7 in PCOS, particularly its impact on pyroptosis. KGN cells were treated with LPS to establish a cell model, and pyroptosis was evaluated using enzyme-linked immunosorbent assay, flow cytometry, and western blotting. The effect of NSUN7 on the m5C modification of NLRP3 was assessed using methylated RNA immunoprecipitation, dual-luciferase reporter assay, and actinomycin D treatment experiment. A PCOS rat model was generated, hormones were detected using ELISA, and pyroptosis was evaluated in the ovaries and primary granulosa cells. The results showed that NSUN7 expression was reduced in patients with PCOS and LPS-treated KGN cells. Silencing of NSUN7 inhibited LPS-induced cell pyroptosis. Moreover, NSUN7 knockdown inhibited m5C methylation of NLRP3 and reduced NLRP3 mRNA stability. Overexpression of NLRP3 reversed the pyroptosis inhibition induced by NSUN7 knockdown. Furthermore, interfering with NSUN7 alleviated hormone abnormalities and suppressed granulosa cell pyroptosis in PCOS rats. In conclusion, silencing of NSUN7 attenuates PCOS progression by inhibiting pyroptosis of granulosa cells by suppressing m5C methylation of NLRP3.
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