INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Jiahui Zhang,Xinrui Luan,Xinpeng Liu,Wenxuan Zhang,Lili Jiang,Junlong Da,Shujian Zhang,Lixue Liu,Yanbo Li,Zhenyu Yang,Yang Hu,Han Jin,Ying Li
FAM20C is elevated in inflamed periodontal tissues and LPS-treated cells. • Fam20c loss sensitizes osteoblasts to Caspase-1/GSDMD pyroptosis. • RNA-seq links Fam20c deficiency to pyroptosis and ER-stress signatures. • Metabolomics reveals purine and amino-acid metabolic remodelling. • Ac-YVAD-CMK reverses inflammatory activation in Fam20c-deficient cells. FAM20C is a secretory-pathway kinase required for mineralized-tissue homeostasis, and FAM20C-associated disease is accompanied by early periodontal inflammation. We investigated whether FAM20C limits Caspase-1-dependent osteoblast pyroptosis during periodontal inflammatory challenge. FAM20C/Fam20c expression was assessed by immunohistochemistry in ligature-induced mouse periodontitis and human gingiva and by RT-qPCR after lipopolysaccharide (LPS) exposure in four cell models. Stable Fam20c-deficient and Fam20c-overexpressing osteoblasts were analysed by transcriptomics, untargeted metabolomics, microscopy, immunofluorescence, RT-qPCR, Western blotting, ELISA and pharmacological Caspase-1 inhibition. FAM20C/Fam20c protein and mRNA increased in inflamed tissues, and LPS induced Fam20c expression. Fam20c deficiency increased ER-stress/Ca 2+ -homeostasis and inflammasome/pyroptosis module scores, reduced osteogenic gene expression and altered purine- and antioxidant-related metabolites. Fam20c loss enhanced LPS-induced cleaved Caspase-1, N-GSDMD and IL-1β/IL-18 release, whereas Fam20c overexpression attenuated these responses. Ac-YVAD-CMK reduced Caspase-1/GSDMD activation and cytokine release in Fam20c-deficient cells. These findings identify Fam20c as a determinant of osteoblast susceptibility to Caspase-1-dependent pyroptosis. Periodontal LPS induces an early FAM20C stress response. Genetic Fam20c deficiency disrupts ER/Ca 2+ and metabolic homeostasis, increases Caspase-1 activation and GSDMD cleavage, and amplifies osteoblast pyroptosis. Ac-YVAD-CMK reduces Caspase-1/GSDMD activation and cytokine release Download: Download high-res image (290KB) Download: Download full-size image
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Science Advances
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2025
·Vol. 11
·期 26
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IF 12.5
Ruizhi Hu,Junchang Qin,Wei Feng,Xinran Song,Hui Huang,Chen Dai,Bo Zhang,Yu Chen
Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn 2+ features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn 2+ release and inhibit pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP channel 1 (MTC1)–related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic reactive oxygen species, inhibiting macrophage pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing other inflammatory diseases.
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高影响因子
Advanced Science
·
2025
·
IF 14.1
Xiaomin Su,Yang Wang,Xifeng Qin,Yaqiong Xiao,Boshu Ouyang,Lina Hu,Lin Kang,Ruizhe Xu,Ce Xu,Zanya Sun,Chenyu Sun,Huishu Guo,Zhiqing Pang,Shun Shen
The high heterogeneity of basal-like breast cancer (BLBC) and the absence of effective therapeutic targets pose ongoing treatment challenges. Pyroptosis, a type of cell death characterized by cell swelling and membrane perforation, offers a promising therapeutic weathervane for BLBC, particularly when induced by physical therapies. In this study, a high-intensity focused ultrasound (HIFU)-driven targeted pyroptosis strategy is developed for BLBC therapy. Through integration of HIFU-driven gene regulation analysis and bioinformatics analysis of pyroptosis-related genes from the TCGA dataset, 20 potential pyroptosis inducers are identified to work synergistically with HIFU. Mitoxantrone, a promising inducer, is encapsulated in platelet membrane-hybridized liposomes to enhance targeted delivery and therapeutic efficacy. Importantly, the combination of HIFU and Plp enhanced tumor delivery of liposomes by 2.46 fold and dramatically inhibited tumor growth, with 50% of female BALB/c mice remaining tumor-free compared to liposome-only treatment. Mechanistically, HIFU significantly downregulated the expression of histone deacetylases 4 and 9, while promoting cathepsin-L (CTSL) gene transcription. Simultaneously, Plp and HIFU synergistically suppressed BCL-2 via CTSL, increasing ROS production. This activated Caspase8 and the NLRP3 inflammasome, leading to GSDMC cleavage and initiating pyroptosis. Collectively, this study provides an innovative pyroptosis therapy strategy combining physical treatment and chemotherapy for BLBC and other refractory diseases.
研究领域:
肿瘤学
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分子生物学
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转化医学
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纳米医学
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细胞死亡机制
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生物信息学
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基因调控
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高影响因子
ADVANCED MATERIALS
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2025
·
IF 26.8
Guangru Li,Xinyue Dai,Yuling Liu,Jinli Chen,Weijie Yu,Ping Li,Luodan Yu,Yu Chen
Recombination of sono-generated charge carriers is a major barrier hindering the effectiveness of piezocatalytic oncotherapy. Herein, ultrathin oxygen vacancy-engineered self-heterojunction bismuth oxysilicate (O v -BOS) nanosheets with alternating hetero-layered nanostructure are constructed for enhanced sono-piezocatalytic tumor therapy. Benefiting from its out-of-plane asymmetry, O v -BOS features an exceptional electromechanical strain coefficient (d * 33 = 203 pm/V), highlighting its outstanding capability as a piezoelectric heterojunction for energy conversion. Particularly, the oxygen vacancy engineering facilitates the spatial redistribution of bands across the alternating [Bi 2 O 2 ] and [SiO 3 ] layers in O v -BOS, promoting effective charge separation and stratified charge storage, thereby further suppressing recombination of sono-generated charge carriers in a manner analogous to heterojunctions. Leveraging this strategy, O v -BOS demonstrates efficient reactive oxygen species production and exhibits superior peroxidase and catalase-like activities compared to the conventional piezoelectric nanocatalysts. Consequently, the enhanced radical generation induced the specific cancer-cell pyroptosis via caspase-3 mediated gasdermin E-dependent pathway. Therefore, the engineered interlayer self-heterojunction provides an efficient strategy for the design and engineering of high-performance piezoelectric nanocatalysts.
研究领域:
纳米技术
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材料科学
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生物医学工程
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肿瘤学
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物理化学
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高影响因子
Acta Pharmaceutica Sinica B
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2025
·
IF 14.6
Shengmei Wang,Ding Ma,Minghua Yang,Ye Zhang,Shengfeng Wang,Wenhu Zhou
Chemotherapy remains a primary treatment option for hepatocellular carcinoma (HCC), yet its clinical benefits are often unsatisfactory. Utilizing arsenic trioxide (ATO) as a model, this study elucidates the role of autophagy inhibition in modulating the cellular response to chemotherapy, shifting cell death from apoptosis to pyroptosis via the caspase-3–GSDME pathway, thereby augmenting the anti-tumor efficacy. Building upon these findings, an ATO nanomedicine delivery system capable of autophagy inhibition to promote pyroptosis for enhanced tumor treatment was developed. Folic acid-modified albumin served as the stabilizer for nano self-assemblies formed through ion pairing between Mn 2+ and ATO, encapsulating DNAzyme (Dz) targeting Beclin 1, a key autophagy regulator. Characterization studies confirmed efficient encapsulation of ATO and Dz within nanoparticles, designed to disintegrate in the intracellular microenvironment, releasing the all-active components, i.e. , ATO, Mn 2+ , and Dz. Mn 2+ acted as a metal cofactor to activate Dz for Beclin 1 mRNA cleavage, inhibiting autophagy and augmenting ATO-induced cell pyroptosis. Elevated cell pyroptosis levels not only enhance ATO’s direct tumor cell killing capacity but also trigger anti-tumor immune responses, synergistically enhancing efficacy. Upon intravenous injection, the nanomedicine accumulated in tumor tissue and targeted liver cancer cells. Compared to free ATO, the nanomedicine exhibited significantly improved in vivo anti-tumor effects, achieving a 100% 45-day survival rate in mice with favorable biosafety profiles. This study offers novel insights into tumor chemotherapy sensitization and presents a promising strategy for ATO nanoformulation development.
研究领域:
肿瘤学
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纳米医学
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药理学
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分子生物学
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生物化学
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免疫学
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JOURNAL OF CONTROLLED RELEASE
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2024
·
IF 10.5
Shiquan Sun,Yong He,Jiaqi Xu,Shaolong Leng,Yu Liu,Huanhuan Wan,Leping Yan,Yunsheng Xu
Despite the fact that immunotherapy has significantly improved the prognosis of melanoma patients, the non-response rate of monoimmunotherapy is considerably high due to insufficient tumor immunogenicity . Therefore, it is necessary to develop alternative methods of combination therapy with enhanced antitumor efficiency and less systemic toxicity. In this study, we reported a cancer cell membrane-coated zeolitic imidazole framework-8 (ZIF-8) encapsulating pyroptosis-inducer oxaliplatin (OXA) and immunomodulator imiquimod (R837) for chemoimmunotherapy. With the assistance of DNA methyltransferase inhibitor decitabine (DCT), upregulated Gasdermin E (GSDME) was cleaved by OXA-activated caspase-3, further inducing tumor cell pyroptosis , then localized antitumor immunity was enhanced by immune adjuvant R837, followed by triggering systemic antitumor immune responses. These results provided a proof-of-concept for the use of cell membrane-coated biomimetic nanoparticles as a promising drug carrier of combination therapy and a potential insight for pyroptosis-based melanoma chemo-immunotherapy.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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癌症生物学
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BIOMATERIALS
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2025
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IF 12.9
Lin Liu,Kaiyan Huang,Xia Sun,Junpeng Shi,Xianggui Yin,Wenpeng Zhao,Peng Lin,Yutong Han,Fangrong Zhang,Weibing Miao,Yun Zhang
Pyroptosis is an effective strategy for inducing inflammatory responses in 'cold' tumors, boosting the efficacy of immunotherapy. Although biodegradable inorganic nanoparticles (BINPs) show great potential in pyroptosis by releasing ions to break intracellular homeostasis, the limited intracellular ion release efficiency restricts pyroptosis level and subsequent immune activation. Herein, by heterovalent substitution strategy, a series of Na 3 ZrF 7 :x%Yb 3+ (NZF:x%Yb, x = 0, 9, and 18) BINPs with tunable intracellular ion release efficiency are synthesized for enhanced pyroptosis and tumor immunotherapy. Specifically, the size of NZF:x%Yb 3+ gradually decrease with increasing Yb 3+ -doped and smaller NZF:x%Yb presents a higher degradation rate and cellular uptake ability, enabling improved intracellular ion release efficiency. This leads to drastic intracellular homeostasis stress and abundant ROS generation, thereby provoking enhanced caspase-1-related pyroptosis. Antitumor experiments in triple-negative breast cancer model confirm that the ultra-small NZF:x%Yb (NZF:18%Yb) with the highest intracellular ion release efficiency shown the most effective antitumor ability, and significant inhibition of distal tumor. This study reveals precise control over the size of NZF:x%Yb is especially vital to achieving pyroptosis-induced immunotherapy, which offers a new perspective for the design of BINPs.
研究领域:
纳米医学
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癌症免疫治疗
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材料科学
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生物医学工程
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Xin Wang,Hao Yin,Ling Fan,Yiqun Zhou,Xiaolong Tang,Xiaojun Fei,Hailin Tang,Juan Peng,Junjun Zhang,Yi Xue,Jianping Luo,Qinglei Jin,Qingjiang Jin
Shionone is a triterpenoid component derived from the herbal medicine Aster tataricus , and it has been reported to possess marked anti-inflammatory properties. The activation of NLRP3 inflammasome plays an important role in cystitis, and the effect of Shionone on NLRP3 inflammasome-dependent pyroptosis remains unclear. In this study, we established an interstitial cystitis (IC) rat model and SV-HUC-1 cell model with CYP or LPS + ATP treatment to mimic inflammation response and induce NLRP3 inflammasome activation. Shionone treatment significantly attenuated the bladder wet weight, score of edema and hemorrhage, enhanced the viability of SV-HUC-1 cell, decreased the rate of pyroptosis. Moreover, Shionone reduced the expression of NF-κB, NLRP3, ASC, Pro-caspase-1, Caspase-1, GSDMD, GSDMD-N at the mRNA and protein levels both in rat and SV-HUC-1 cell model, demonstrating NLRP3 inflammasome pathway was blocked and pyroptosis degree was reduced. These results indicated that Shionone could alleviate interstitial cystitis in Rat model and enhancing the viability of SV-HUC-1 cells via NF-κB/NLRP3/GSDMD-N pathway, which illustrated that Shionone could be used as a drug candidate for the treatment of interstitial cystitis.
研究领域:
药理学
·
免疫学
·
泌尿学
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高影响因子
Frontiers in Aging Neuroscience
·
2022
·
IF 5.702
Cai Yawen,Chai Yuhui,Fu Yu,Wang Yingdi,Zhang Yiming,Zhang Xue,Zhu Lingpeng,Miao Mingxing,Yan Tianhua
Amyloid β-protein (Aβ) is reported to activate NLRP3 inflammasomes and drive pyroptosis, which is subsequently involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). To date, the pathogenesis of AD is unfortunately insufficiently elucidated. Therefore, this study was conducted to explore whether Salidroside (Sal) treatment could benefit AD by improving pyroptosis. Firstly, two animal models of AD, induced, respectively, by Aβ1-42 and D-galactose (D-gal)/AlCl3, have been created to assist our appreciation of AD pathophysiology. We then confirmed that pyroptosis is related to the pathogenesis of AD, and Sal can slow the progression of AD by inhibiting pyroptosis. Subsequently, we established the D-gal and Nigericin-induced PC12 cells injury model in vitro to verify Sal blocks pyroptosis mainly by targeting the NLRP3 inflammasome. For in vivo studies, we observed that Aβ accumulation, Tau hyperphosphorylation, neurons of hippocampal damage, and cognitive dysfunction in AD mice, caused by bilateral injection of Aβ1-42 into the hippocampus and treatments with D-gal combine AlCl3. Besides, accumulated Aβ promotes NLRP3 inflammasome activation, which leads to the activation and release of a pro-inflammatory cytokine, interleukin-1 beta (IL-1β). Notably, both Aβ accumulation and hyperphosphorylation of Tau decreased and inhibited pyroptosis by downregulating the expression of IL-1β and IL-18, which can be attributed to the treatment of Sal. We further found that Sal can reverse the increased protein expression of TLR4, MyD88, NF-κB, P-NF-κB, NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18 in vitro. The underlying mechanism may be through inhibiting TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway. Our study highlights the importance of NLRP3 inflammasome-mediated pyroptosis in AD, and how the administration of pharmacological doses of Sal can inhibit NLRP3 inflammasome-mediated pyroptosis and ameliorate AD. Thus, we conclude that NLRP3 inflammasome-mediated pyroptosis plays a significant role in AD and Sal could be a therapeutic drug for AD.
研究领域:
神经科学
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药理学
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分子生物学
·
炎症
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高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Jing Lu,Ziheng Chen,Xiujuan Bu,Shanshan Chen,Shuang Guan
Elaidic acid (EA, C18:1 trans) is a kind of principal Trans fatty acid (TFA) and is widely found in processed food. Pyroptosis is a form of programmed cell death , distinct from apoptosis and traditional necrosis. Excessive pyroptosis could induce body injury and serious inflammation. However, the effect of EA on pyroptosis has not been reported. In the study, we found that EA exposure caused liver damage and hepatocyte pyroptosis by testing GSDMD-N, Caspase 1 , IL-18, and IL-1β in mice and HepG2 cells. Further exploring the mechanisms, we found that EA-induced pyroptosis depended on Cathepsin B (CTSB)-mediated NLRP3 inflammasome activation. Cell autophagy was closely related to lysosomes . Our study revealed that EA promoted hepatocyte autophagy, and activated autophagy induced lysosomal membrane permeabilization (LMP) and CTSB leakage . Inhibition of autophagy by 3-MA mitigated the CTSB leak, reduced the activation of the NLRP3 inflammasome, and then attenuated the EA-induced pyroptosis. In summary, these results indicated that EA induced hepatocyte pyroptosis via autophagy-CTSB-NLRP3 inflammasome pathway. The study revealed new insights into the toxicity mechanism of EA.
研究领域:
毒理学
·
细胞生物学
·
分子生物学
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肝病学
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高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2026
·
IF 3.6
Shangxiang Feng,Kun Song,Hao Zhang,Zhuoqun Wang,Yuchi Zhao,Zhongyuan Zhao,Chao Wan
This study investigated the effects of Aureusidin on extracellular matrix (ECM) degradation and pyroptosis of chondrocytes in osteoarthritis. Network pharmacology, molecular docking, and pull-down assays were initially conducted to explore the target of Aureusidin. Subsequently, Sprague-Dawley rats underwent anterior cruciate ligament transection (ACLT) received oral administration of Aureusidin. Cartilage damage was evaluated histopathologically by H&E and Safranin O-fast green staining. Primary rat chondrocytes were treated with Aureusidin under IL-1β stimulation. Pyroptotic morphology was observed under light microscopy. Propidium iodide staining and flow cytometry were conducted to evaluate membrane rupture. The expression of markers associated with ECM degradation and pyroptosis was analyzed by qRT-PCR, Western blot, immunohistochemistry, and ELISA. Caspase-3 was identified as a target for Aureusidin. Aureusidin (5, 10, 20 mg/kg) alleviated ACLT-induced cartilage damage and ECM degradation. It reduced the OARSI score and serum levels of CTX-II and COMP, while upregulating the expression of Col2a1 and Acan , and downregulating Adamts5 , Mmp13 , and Mmp3 . Aureusidin also mitigated atypical pyroptosis, evidenced by inhibited expression of GSDME-N, Caspase-3, and Cleaved-Caspase-3, and decreased levels of IL-1β and IL-18. In IL-1β-stimulated primary chondrocytes, Aureusidin (5, 10, 20 μM) attenuated ECM degradation and Caspase-3/GSDME-mediated pyroptosis. Treating chondrocytes with the Caspase-3 inhibitor Z -DEVD-FMK under IL-1β-stimulated conditions alleviated ECM degradation and pyroptosis, but the additional application of Aureusidin did not provide further inhibition. Aureusidin has the potential to inhibit ECM degradation and Caspase-3/GSDME-mediated chondrocyte pyroptosis during osteoarthritis progression. Its therapeutic effects are dependent on binding to and modulating the Caspase-3.
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高影响因子
LIFE SCIENCES
·
2026
·
IF 6.4
Zhaoxu Qiu,Huaxing Zhang,Bo Tan,Qian Chen,Huizi Gao,Yuhan Yao,Yangxuan Peng,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xu Teng,Yanzhuo Ma,Yuming Wu,Sheng Jin
Aims The present study was aimed to investigate whether trimethylamine N-oxide (TMAO) contributed to cardiac aging and to explore the underlying mechanism. Materials and methods Male C57BL/6 J mice were randomly divided into four age groups (3, 12, 18, and 24 months) to assess the cardiac function. Markers of senescence, oxidative stress, and the protein expression of pyroptosis were also measured. To test the hypothesis that TMAO promoted cardiac aging, 8-week-old mice were intraperitoneally injected with TMAO for 1–3 months and 3,3-dimethyl-1-butanol was administered in drinking water starting from 15 months of age for three months to inhibit TMAO production. Gasdermin D (GSDMD) knockout mice were also used. Key findings Plasma TMAO levels increased with age and correlated with upregulation of cardiac senescence markers, diastolic dysfunction, cardiac fibrosis, and elevated plasma brain natriuretic peptide levels. Starting from 2 months of TMAO treatment, impairment of cardiac diastolic function and progression of cardiac fibrosis were observed alongside the upregulation of senescence marker proteins expression. Mechanistically, TMAO promoted cardiac oxidative stress and activated the NLRP3-mediated pyroptosis pathway. Genetic ablation of GSDMD abolished TMAO-associated cardiac aging. Furthermore, pharmacological inhibition of TMAO production in aged mice attenuated oxidative stress, suppressed NLRP3-mediated pyroptosis activation, and alleviated cardiac aging. Significance This study revealed that plasma TMAO levels progressively increase with age in mice and TMAO contributed to cardiac aging in a time-dependent manner through NLRP3-mediated pyroptosis driven by oxidative stress. Moreover, the inhibition of TMAO generation might offer a basis for future therapeutic strategies. Download: Download high-res image (146KB) Download: Download full-size image
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