Cell Death Discovery
·
2020
·Vol. 6
·期 1
·1-13
·
IF 4.114
Zheng Tao,Zhao Chuchu,Zhao Baowen,Liu Hanruo,Wang Shijian,Wang Liyuan,Liu Ping
Macular corneal dystrophy (MCD) is ascribed to mutations in the carbohydrate sulfotransferase ( CHST6 ) gene affecting keratan sulfate (KS) hydrophilicity and causing non-sulfated KS to precipitate in keratocytes and the corneal stroma. We investigated roles for inflammatory responses in MCD pathogenesis by examining the lysosomal-autophagy pathway and activation of pyroptosis in MCD keratocytes. Normal and lesioned keratocytes were obtained from MCD patients undergoing corneal transplantation. The keratocytes were subjected to gene sequencing, RT-PCR, western blotting, transmission electron microscopy, histological staining, induction and inhibition assays of autophagy and pyroptosis, CCK-8 and LysoTracker Green DND-26 labeling, and flow cytometry. A novel homozygous MCD mutation was identified in a family from Northeast China; the mutation was distinguished by cytoplasmic vacuolation, cell membrane disruption, electron dense deposits, and deposition of a band of Periodic acid-Schiff and Alcian blue-positive material in the keratocytes and stroma layer. KS protein levels were decreased, expression of p62 and LC3-II proteins was enhanced, cathepsin D expression was declined and the LysoTracker Green DND-26 signal was dramatically reduced in MCD keratocytes. Bafilomycin-A1 treatment significantly increased caspase-1 and Pro-IL-1β expression in normal and MCD keratocytes. Nod-like receptors pyrins-3 (NLRP3), caspase-1, Pro-IL-1β, and IL-1β levels were pronouncedly elevated in cells exposed to H 2 O 2 . Ac-YVAD-CMK treatment reversed this expression in normal and MCD keratocytes. Suppression of the autophagic degradation of non-sulfated KS by impaired autophagic flux in MCD keratocytes triggers pyroptosis. Amelioration of impaired autophagy and restraint of pyroptosis may, therefore, have therapeutic efficacy in the treatment of MCD.
研究领域:
眼科学
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细胞生物学
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分子生物学
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病理学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Zheng Yuan,Ziteng Wang,Haidong Shen,Quanlong Zhang,Jiahui Zhou,Jinzhou Cai,Lin Hu,Zetong Chen,Qing He,Kai Zhang,Kai Yang,Pei Pei,Jin Zhou
A pH-responsive nanoplatform was developed to enhance gastric cancer chemo-immunotherapy. • Tumor acidity-triggered charge reversal improved intracellular delivery of oxaliplatin and BAPTA-AM. • Calcium chelation blocked pyroptosis reversibility and amplified immunogenic cell death. • The nanoplatform weakened tumor stemness and reshaped the immune microenvironment. The clinical response rate of combined chemotherapy and immunotherapy in gastric cancer remains unsatisfactory, largely due to insufficient release of tumor antigens and immunogenic cell death signals under treatment-tolerant conditions, as well as immune evasion driven by cancer stem cells (CSCs). To address this, this study constructed a membrane-affinity intelligent nanodelivery system (pHP + -O/B) that responds to the acidic tumor microenvironment, for the co-delivery of oxaliplatin and the calcium ion chelator BAPTA-AM. Under acidic tumor conditions, pHP + -O/B undergoes PEG detachment and exposes a positively charged core, enhancing its interaction with gastric cancer cell membranes and improving intracellular drug delivery. Mechanistically, oxaliplatin induces GSDME-mediated pyroptosis, while BAPTA-AM synergistically amplifies this effect by blocking calcium dependent membrane repair processes, thereby significantly promoting the release of immunogenic molecules such as HSP70 and HMGB1 and remodeling the tumor immune microenvironment. Further investigations reveal that this strategy effectively suppresses Wnt/β-catenin associated stemness signaling, reduces the CSCs population, enhances DC maturation and promotes T-cell activation. Patient-derived xenograft (PDX) models further confirmed the antitumor efficacy of pHP + -O/B and its ability to enhance pyroptosis and suppress tumor stemness. In summary, we present a nano-delivery strategy that synergistically amplifies pyroptosis and suppresses tumor stemness, thereby enhancing chemo-immunotherapy efficacy in gastric cancer.
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高影响因子
JOURNAL OF RARE EARTHS
·
2026
·
IF 9.6
Shuyu Liu,Pengye Du,Jianhao Zheng,Pengpeng Lei,Hongjie Zhang
Mitochondrial Ca 2+ overload is a promising strategy to induce pyroptosis. However, exogenous introduction of Ca 2+ -regulation is often inefficient due to the body’s homeostatic regulatory properties and the acidic microenvironment of tumor. Here, we achieve efficient mitochondrial endogenous Ca 2+ overload for inducing pyroptosis by controlling the extracellular Ca 2+ influx and endoplasmic reticulum (ER) Ca 2+ leakage. Specifically, on the one hand, the singlet oxygen produced by near-infrared irradiation of upconversion nanoparticles stimulate the opening of TRPV1 channel on the cell membrane surface to influx Ca 2+ ; on the other hand, the opening of Ryanodine Receptor channel on the ER by tunicamycin leads to Ca 2+ leakage. Under the dual action of extracellular Ca 2+ influx and ER Ca 2+ leakage, the surge of Ca 2+ concentration in the cytoplasm further induces Ca 2+ overload in mitochondria, which triggers pyroptosis through the caspase 1/gasdermin D-dependent channel. Importantly, the onset of pyroptosis induces a strong immune response, ultimately enabling not only efficient tumor therapy, but also inhibition of lung metastasis.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Jiahao Hu,Yuejie Lu,Zhengyang Tan,Jialu Lang,Shihui Wu,Di Chen,Jucong Zhang,Xiaochuan Wu,Qi Zhu,Yuanyan Huang,Jiawen Zhu,Zijian Shen,Xiaolei Hao,Wenzhe Ma,Luwen Zhu,Jiansong Ji,Yongzhong Du
The efficacy of immune checkpoint blockade (ICB) is often constrained by insufficient tumor antigenicity and consequent weak immune activation. Among immunogenic cell death (ICD) modalities, gasdermin-mediated pyroptosis presents a promising strategy to counteract this limitation and potentiate ICB. However, it remains challenging to engineer nanoplatforms that reliably induce pyroptosis via coordinated activation of multiple pathways. Here, we report a sialic acid-functionalized lipid nanoparticle (LNP) that co-delivers GSDME mRNA and a self-assembling small molecule (1541B) as a potent pyroptosis amplifier. Delivered GSDME mRNA bypasses epigenetic silencing and replenishes the pyroptotic substrate, while 1541B self-assembles intracellularly into nanofibers that directly activate caspase-3, cleaving GSDME to initiate non-canonical pyroptosis. Moreover, these nanofibers disrupt mitochondrial function, leading to caspase-1-mediated GSDMD cleavage, thereby amplifying pyroptotic cell death via the canonical pathway. This dual-pathway engagement enhances the release of pro-inflammatory cytokines and remodels the tumor immune microenvironment. As a result, this nano-pyroptosis inducer overcomes resistance to anti-PD-1 therapy, triggering potent systemic anti-tumor immunity and significantly inhibiting tumor growth. Overall, our findings establish a novel therapeutic paradigm for reversing ICB resistance via orchestrated pyroptosis amplification.
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Ming Yue,Keying Zhu,Kunyu Zhan,Jinjie Zhang,Yuanbin Zhang,Kun Tian,Wenbiao Zheng,Xiaogang Chen,Hongfeng Ruan
Chlorpyrifos (CPF), a widely used pesticide, poses significant risks to human and animal health through environmental and food exposure. While its detrimental effects on the nervous, cardiovascular, and endocrine systems are well-documented, its impact on knee joint health remains poorly understood. In this study, 4-week-old male C57BL/6 mice were exposed to CPF via intragastric administration at doses of 3 and 6 mg/kg for durations of 4 and 8 weeks. Osteoarthritis (OA) severity and associated molecular alterations in knee joints were evaluated by hematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, immunohistochemistry, and immunofluorescence. Our results showed that CPF exposure led to knee joint injury, characterized by articular cartilage degeneration and subchondral bone loss. Notably, CPF induced both apoptosis and pyroptosis of chondrocytes via activation of the NF-κB signaling pathway, with pyroptosis appearing to be the predominant mechanism at lower doses and shorter exposure durations. Collectively, our findings provide novel insights into CPF's role in exacerbating articular cartilage degeneration by activating chondrocyte pyroptosis, underscoring its contribution to knee joint damage and OA-like progression.
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高影响因子
Advanced Science
·
2026
·
IF 14.1
Dan Zhao,Lingling Zhang,Yue Wen,Lianghui Cheng,Sidan Tian,Fanling Meng,Liang Luo
Pyroptosis holds great promise for evoking robust anti‐tumor immunity, but many pyroptosis induction strategies rely on caspase‐3 (Casp‐3) activation and face challenges of the immunosuppressive nature of apoptosis and the frequent silencing of gasdermin E (GSDME), a substrate of Casp‐3, in tumors. Here, we report a strategy to rewire the pyroptotic pathway by bypassing Casp‐3 to directly activate gasdermin D (GSDMD). We identify a small‐molecule agonist, (E)‐2,3‐diiodobut‐2‐ene‐1,4‐diol (DIBDO), which undergoes deiodination to release iodide ions upon activation by the tumor‐abundant nucleophile glutathione, thereby catalytically generating singlet oxygen and molecular iodine. This cascade induces oxidative damage that downregulates key mediators of caspase‐9 and caspase‐8 pathways, thereby down‐regulating Casp‐3 activation. This mechanism selectively triggers GSDMD‐mediated pyroptosis, provoking robust immunogenic cell death and inflammatory cytokine release to reconfigure the tumor immune microenvironment. In murine tumor models, DIBDO enhances tumor infiltration of cytotoxic T cells and synergizes with checkpoint blockade therapy to suppress both primary and distal tumors. It can also serve as an in situ or exogenous vaccine to elicit potent and durable antitumor immunity. This work presents a paradigm‐shifting approach to cancer immunotherapy by decoupling pyroptosis from Casp‐3 dependence, offering a promising avenue to expand the scope of immunogenic cell death‐based treatments. This work introduces a small‐molecule agonist, DIBDO, that bypasses Casp‐3 to directly trigger GSDMD‐mediated pyroptosis in tumors. Activated by glutathione, DIBDO generates singlet oxygen and molecular iodine, blocking Casp‐3 pathways and inducing immunogenic cell death. This reconfigures the tumor microenvironment, transforms the tumor cells into in situ or exogenous vaccine, offering a novel paradigm for cancer immunotherapy.
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高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Shiyan Bai,Tao Zeng,Yana Liu,Xiao Fang,Sang Lin,Xiuping Cao,Shiqing Li,Qi Chen,Chunhua Lu
Pyroptosis, an immunogenic cell death mediated by Gasdermin proteins, enhances antitumor immune responses and reshapes the tumor microenvironment. Among the Gasdermin proteins, Gasdermin E (GSDME) can be cleaved by caspase-3 or Granzyme B (GZMB), releasing the N-terminal GSDME fragment (GSDME-N) to initiate pyroptosis. However, the effectiveness of GSDME-induced pyroptosis is often limited due to GSDME silencing via methylation and underutilizing the concurrent cleavage of GSDME by caspase-3 and GZMB. Herein, an innovative integrated platform based on engineered exosomes, termed NK-RG-exo, is developed. NK-RG-exo is engineered by loading the methyltransferase inhibitor RG108 into exosomes derived from natural killer cells that naturally express GZMB. In tumor cells, RG108 restores GSDME expression by demethylation, and GZMB directly cleaves GSDME and triggers caspase-3 activation that, in turn, also cleaves GSDME. These dual pathways ensure substantial release of GSDME-N to initiate pyroptosis. Furthermore, GSDME-N disrupts mitochondrial membranes, releasing Cytochrome C to activate caspase-3, which further cleaves GSDME again, thereby creating a positive feedback loop. In an orthotopic breast cancer mouse model characterized by limited immune cell infiltration, NK-RG-exo significantly induces antitumor immune responses by intense pyroptosis. The proposed strategy effectively overcomes the immunosuppressive tumor microenvironment, holding significant promise in cancer therapy.
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高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2025
·
IF 3.1
You Xujun,Li Honghan,Li Qixin,Zhang Qing,Cao Yiguo,Fu Wei,Wang Bin
Prostate cancer (PCa) is an epithelial malignancy affecting the prostate gland. Astragaloside IV combined with polypeptide extract from scorpion venom (PESV) has been reported to inhibit the growth of PCa. This study aimed to investigate the mechanisms by which this combination mitigates the progression of PCa. Bioinformatic analysis was utilized to investigate the correlation between zinc finger DHHC-type containing 1 (ZDHHC1) expression and PCa progression. The extent of pyroptosis in PCa cells was assessed by measuring cell viability, IL-1β and IL-18 secretion, LDH release, and HMGB1 content. PCa mouse models were constructed by subcutaneous injection of DU145 or PC-3 cells into nude mice, with subsequent monitoring of tumor weight and volume. ZDHHC1 expression was significantly lower in PCa patient tissues, which correlated with a poor prognosis. ZDHHC1 overexpression inhibited PC-3 and DU145 cell viability and increased IL-1β, IL-18, LDH, and HMGB1 levels in cell supernatants. Notably, the pyroptosis inhibitor LDC7559 partially reversed these effects. Co-IP assay demonstrated an interaction between ZDHHC1 and GSDMD. ZDHHC1 overexpression significantly enhanced GSDMD palmitoylation-mediated membrane translocation and pyroptosis; however, this effect was partially reversed by the palmitoylation inhibitor 2-BP. The combination of Astragaloside IV and PESV promoted GSDMD membrane translocation and pyroptosis in PCa cells, with ZDHHC1 knockdown partially reversing the effects of Astragaloside IV-PESV. Furthermore, treatment with Astragaloside IV-PESV significantly inhibited tumor tissue growth in tumor-bearing nude mouse models. Astragaloside IV-PESV enhances palmitoylation-mediated membrane translocation of GSDMD-N by upregulating ZDHHC1 expression, thereby facilitating pyroptosis in PCa cells and attenuating PCa progression.
研究领域:
肿瘤学
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细胞生物学
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药理学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-22
·
IF 12.6
Yang Ningning,Hua Rongrong,Lai Yingying,Zhu Peijun,Ding Jian,Ma Xianhui,Yu Gaoxiang,Xia Yiheng,Liang Chao,Gao Weiyang,Wang Zhouguang,Zhang Hongyu,Yang Liangliang,Zhou Kailiang,Ge Lu
In the field of large-area trauma flap transplantation, preventing avascular necrosis remains a critical challenge. Key mechanisms for improving flap viability include angiogenesis promotion, oxidative stress inhibition, and cell death prevention. Recently, two-dimensional ultrathin Ti 3 C 2 T X (MXene) nanosheets have gained attention for their potential contributions to these processes, though MXene’s physiological impact on flap survival had not been previously investigated. This study is the first to confirm MXene's biological effects on the ischaemic microenvironment post-skin flap transplantation. Findings indicated that MXene significantly decreased the necrotic area in ischaemic flaps (37.96% ± 2.00%), with reductions of 30.40% ± 1.86% at 1 mg/mL and 20.19% ± 2.11% at 2 mg/mL in a concentration-dependent manner. Mechanistically, MXene facilitated in situ angiogenesis, mitigated oxidative stress, suppressed pro-inflammatory pyroptosis, and activated the PI3K-Akt pathway, particularly influencing vascular endothelial cells. Comparative transcriptome analysis of skin tissues with and without MXene treatment provided additional evidence, highlighting mechanisms such as pro-inflammatory pyroptosis, ROS metabolic processes, endothelial cell proliferation regulation, and PI3K-Akt signaling pathway activation. Overall, MXene demonstrated biological activity, effectively promoting ischaemic flaps survival and presenting a novel strategy for addressing ischaemic necrosis in skin flaps. Graphical abstract
研究领域:
医学
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生物材料学
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分子生物学
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PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2025
·
IF 2.8
Shuge Shu,Xinting Chen,Jiawen Ren,Xiangyu Yu,Hao Zhang,Yongquan Yu
Glyphosate is reported to compromise the central nervous system and induce behavioral disorders in mammals. However, evidence is deficient with respect to the potential mechanisms involved. In this study, C57BL/6 mice were orally exposed to glyphosate at doses ranging from 0 to 200 mg/kg/day for 16 weeks. The results of behavioral tests showed that glyphosate decreased time spent and distance traveled within the central area of open field test, decreased the retention time and number of entries into the open arms, and increased the retention time and number of entries into the close arms of elevated plus maze test. The expressions of anxiety-related genes htr5 , htr6 , and tmem132d were also significantly upregulated by glyphosate. This behavioral phenotype was linked to the permeation of glyphosate into the brain via disrupting the functional tight junctions of blood–brain barrier (BBB). As a result, glyphosate directly compromised the morphological structure of neurons, increased the number of IBA-1 microglia, and activated the expression of NLRP3-mediated pyroptosis pathway (NLRP3, Caspase-1, GSDMD, and IL-18) in the hippocampus of mice. Moreover, the glyphosate-induced activation of NLRP3 pathway in microglia was markedly reversed by NLRP3 inhibitor MCC950. The conditional mediums from glyphosate-treated BV2 cells aggravated the cytotoxicity of HT-22 neurons, which was also rescued by MCC950. In conclusion, this work demonstrated that microglia-mediated activation of NLRP3 pyroptosis pathway plays a detrimental role in glyphosate-behavioral disorders and neuron damage. These findings provide novel evidence for glyphosate-induced neurotoxicity and support the growing association between glyphosate exposure and neurobehavioral disorders in humans.
研究领域:
神经科学
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毒理学
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分子生物学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-18
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IF 12.6
Li Xiaoyan,Wang Ying,Cao Xinyue,Song Xinran,Chen Liang,Chang Meiqi,Chen Yu,Huang Bingcang
Background Reactive oxygen species (ROS)-mediated pyroptosis provides a robust strategy for overcoming apoptosis resistance in breast cancer therapy. Nevertheless, the low efficiency of pyroptosis remains an undeniable challenge. Overcoming this obstacle necessitates the creation of innovative approaches and nanocatalysts to boost ROS generation. Herein, the distinct lanthanum-doped BiFeO 3 (La-BFO) piezoelectric nanozymes are rationally designed and engineered for the specific cell pyroptosis of breast cancer through inducing the amplified production of ROS and releasing La ions. Results The introduction of La reduces the recombination rate of electron-hole pairs through narrowing the bandgap and creating the oxygen vacancy of BFO, improving the harmful ROS generation efficiency. Importantly, the released La ions robustly disrupt the lysosomal membrane, ultimately inducing cell pyroptosis, in combination with ROS-induced biological effect. Conclusion In vitro and in vivo antineoplastic results confirm the desirable therapeutic effect on combating tumor. Especially, the iron and bismuth elemental components endow the nanocomposites with dual-mode computed tomography/magnetic resonance imaging ability, guaranteeing the potential therapeutic guidance and monitoring. Graphical
研究领域:
生物医学工程
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肿瘤学
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材料科学
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DOI
PubMed
高影响因子
AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
·
2024
·Vol. 92
·期 1
·e13893
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IF 2.5
Yongmei Peng,Yanan Xu,Sainan Li,Mingkun Shao,Zijia Shen,Wenjin Qi
Problem Vulvovaginal candidiasis (VVC) is a common mucosal fungal infection, and Candida albicans is the main causative agent. The NLRP3 inflammasome plays an important role in VVC, but the underlying mechanism is unknown. Method of Study Vaginal epithelial cells were divided into three groups: control, C. albicans strain SC5314 (wild-type, WT), and WT+ Matt Cooper Compound 950 (MCC950, a specific NLRP3 inhibitor). After human vaginal epithelial cells were pretreated with 1 µmol/L MCC950 for 2 h, C. albicans (MOI = 1) was cocultured with the human vaginal epithelial cells for 12 h. The cell supernatants were collected, LDH was detected, and the IL-1β and IL-18 levels were determined by ELISA. The expression of the pyroptosis-related proteins NLRP3, Caspase-1 p20 and GSDMD was measured by Western blotting analysis. The protein expression of the pyroptosis-related N-terminus of GSDMD (GSDMD-N) was detected by immunofluorescence. Results In this study, we showed that the WT C. albicans strain induced pyroptosis in vaginal epithelial cells, as indicated by the LDH and proinflammatory cytokine levels and the upregulated levels of the pyroptosis-related proteins NLRP3, Caspase-1 p20, and GSDMD-N. MCC950 reversed the changes in the expression of these proteins and proinflammatory cytokines in vaginal epithelial cells. Conclusion C. albicans activated the NLRP3 inflammasome to induce vaginal epithelial cell pyroptosis. MCC950 inhibited the NLRP3 inflammasome, reduced vaginal epithelial cell pyroptosis, and decreased the release of inflammatory cytokines.
研究领域:
微生物学
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免疫学
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细胞生物学
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传染病学
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DOI
PubMed
高影响因子
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