Frontiers in Immunology
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2026
·
IF 7
Jianlong Li,Zhe Li,Pengran Wang,Zhian Jiang
PurposeMyocardial ischemia-reperfusion (I/R) is characterized by myocardial cell death and exacerbated inflammatory responses that seriously affect cardiac function and patient prognosis. Limonin is a natural compound extracted from citrus fruits and has various biological activities, including anti-inflammatory and antioxidant activities. However, the role and mechanism of action of limonin in myocardial I/R injury remain unclear. This study aimed to explore the effects and underlying mechanisms of action of limonin on myocardial cell pyroptosis and inflammatory responses in mouse myocardial I/R injury.MethodsBy analyzing the GSE225105 dataset in the Gene Expression Omnibus database, differentially expressed genes in I/R injury were screened and combined with the target genes of limonin in the Comparative Toxicogenomics Database. In the in vitro experiments, The oxygen-glucose deprivation/reoxygenation (OGD/R) model was used to simulate I/R injury in in vitro experiments.ResultsLimonin significantly inhibited OGD/R-induced pyroptosis and the release of inflammatory factors in AC16 myocardial cells, and these effects could be reversed by the caspase-3/gasdermin E (GSDME) pathway activator triclabendazole. Using in vivo experiments, we established a myocardial I/R model in C57BL/6 mice and found that limonin pretreatment improved cardiac function-related indicators, reduced myocardial tissue damage and inflammatory responses, inhibited apoptosis, and reduced myocardial fibrosis. This mechanism is closely related to the inhibition of caspase-3/GSDME pathway activation.ConclusionThis study revealed the protective effects of limonin in reducing myocardial I/R injury by inhibiting the caspase-3/GSDME pathway, thereby providing a theoretical basis for the development of limonin-based myocardial protection strategies.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·795
·
IF 12.6
Zhang Yuanfeng,Yang Enguang,Zhang Xinyu,Shi Yibo,Fan Guangrui,Wang Yuhan,Tian Junqiang,Wang Hanzhang,Dong Zhilong,Wang Yingru,Cheng Liang,Zhao Zhiwen,Zhang Yonghai,Wang Baodui,Wang Zhiping
Background Juglone, a natural naphthoquinone compound, exhibits potent anticancer activity but faces clinical limitations due to poor solubility, low bioavailability, and systemic toxicity. While tumor microenvironment-responsive drug activation strategies offer a promising solution, achieving precise spatial control over the conversion of non-toxic precursors into cytotoxic agents remains a significant challenge. Methods We developed DHN@Pt/PtMBCPsNSs, a platinum (Pt)-methylene blue (MB)- based nanoscale sonosensitizer, to enable ultrasound-triggered on-demand juglone synthesis within tumors. The system was evaluated in bladder cancer models including cell lines, patient-derived organoids (PDOs) and patient-derived tumor xenograft (PDX) models, assessing tumor uptake, intracellular distribution, hypoxia modulation (“H 2 O 2 -O 2 -¹O 2 ” cascade), oxidative stress markers (SOD, GSH, MDA, GSSG), and cell death pathways (apoptosis/pyroptosis). Transcriptome sequencing was performed to elucidate molecular mechanisms. Results DHN@Pt/PtMBCPsNSs were internalized by UMUC-3 and T24 cells and primarily accumulated within the mitochondrial compartments. The platinum-based components catalytically exhausted GSH via redox cycling. DHN@Pt/PtMBCPsNSs triggered the production of O 2 and ¹O 2 after local US irradiation, alleviating hypoxia and selectively converting dihydroxynaphthalene (DHN) to juglone in tumors, which reducing the systemic toxicity of juglone. The nanosystem further disrupted cellular redox balance by triggering depletion of antioxidant defenses (SOD and GSH) and reducing the ratio of GSH/GSSG. In vitro cell experiments and PDOs experiments demonstrated that DHN@Pt/PtMBCPsNSs combined with US irradiation can significantly inhibit bladder cancer cell proliferation, induce apoptosis, and regulate pyroptosis via the ROS-mediated caspase 3/GSDME signaling pathway. In the PDX model, DHN@Pt/PtMBCPsNSs accumulated at the tumor site and significantly inhibited tumor growth under US irradiation. Conclusions As a novel sonosensitizer and pyroptosis inducer, DHN@Pt/PtMBCPsNSs achieve a precise synergistic effect of chemotherapy and sonodynamic therapy within cells, while minimizing adverse effects on normal cells and overcoming the limitations associated with natural chemotherapeutic agents. This approach may advance clinical translation of natural anticancer agents. Graphical
研究领域:
肿瘤学
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纳米医学
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分子生物学
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转化医学
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药理学
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泌尿肿瘤学
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细胞死亡机制
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Pingting Wu,Weilai Chen,Jie Li,Jiayi Xing,Haote Wu,Jingyang Tong,Ping Chen,Haibin Tong,Yongping Chen,Chenwei Pan
Acetaminophen (APAP) overdose causes acute liver injury (ALI) by triggering regulated hepatocyte death. While Imperata cylindrica (Imperatae Rhizoma) (IR) is used in traditional medicine for its hepatoprotective effects, its active compounds and their capacity to modulate this pyroptotic switch remain unknown. In the present study, friedelin (FRI) and 6-methoxyflavone (6-METH) were identified as the principal active compounds of IR, and their protective effects against APAP-induced ALI were evaluated in vivo and in vitro. The results showed that both FRI and 6-METH significantly ameliorated APAP-induced liver injury and reduced hepatocyte death. Mechanistically, their hepatoprotective effects were associated with AKT1-dependent activation of the PI3K/AKT pathway, accompanied by suppression of Caspase-3/ Gasdermin E (GSDME) signaling and attenuation of apoptosis and pyroptosis. Moreover, pharmacological inhibition or genetic silencing of AKT1 markedly weakened these protective effects. Taken together, these findings suggest that FRI and 6-METH are major hepatoprotective constituents of IR and that modulation of the AKT1-mediated Caspase-3/GSDME pathway may contribute to their protective actions against APAP-induced ALI. These findings validate its active compounds as promising therapeutic leads for ALI.
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
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IF 2.5
Juanjuan Zhu,Wenmin Tang,Xian Wu,Mao Mu,Quan Zhang,Xueke Zhao
Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1β, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Small
·
2023
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IF 13.3
Jiahao Hu,Yuchan You,Luwen Zhu,Jucong Zhang,Yanling Song,Jingyi Lu,Xinyi Xu,Xiaochuan Wu,Xiajie Huang,Xiaoling Xu,Yongzhong Du
The efficacy of immune checkpoint blockade (ICB) in promoting an immune response against tumors still encounters challenges such as low response rates and off-target effects. Pyroptosis, an immunogenic cell death (ICD) mechanism, holds the potential to overcome the limitations of ICB by activating and recruiting immune cells. However, the expression of the pyroptosis-related protein Gasdermin-E(GSDME) in some tumors is limited due to mRNA methylation. To overcome this obstacle, sialic acid-functionalized liposomes coloaded with decitabine, a demethylation drug, and triclabendazole, a pyroptosis-inducing drug are developed. This nanosystem primarily accumulates at tumor sites via sialic acid and the Siglec receptor, elevating liposome accumulation in tumors up to 3.84-fold at 24 h and leading to the upregulation of pyroptosis-related proteins and caspase-3/GSDME-dependent pyroptosis. Consequently, it facilitates the infiltration of CD8 + T cells into the tumor microenvironment and enhances the efficacy of ICB therapy. The tumor inhibition rate of the treatment group is 89.1% at 21 days. This study highlights the potential of sialic acid-functionalized pyroptosis nanotuners as a promising approach for improving the efficacy of ICB therapy in tumors with low GSDME expression through epigenetic alteration and ICD.
研究领域:
肿瘤学
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免疫学
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药学
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分子生物学
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2021
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IF 10.588
Caiying Zhang,Zhisheng Hu,Ruiming Hu,Shaoxing Pi,Zejing Wei,Chang Wang,Fan Yang,Chenghong Xing,Gaohui Nie,Guoliang Hu
Pyroptosis and autophagy are two different biological processes that determine cell fates. Our previous studies revealed that pyroptosis and autophagy were involved in cytotoxicity co-induced by molybdenum (Mo) and cadmium (Cd) in duck renal tubular epithelial cells, but crosstalk between them is unclear. Hence, the cells were treated with 500.0 μM Mo, 4.0 μM Cd, 10.0 μM Z-YVAD-fluoromethylketone (YVAD), 2.5 μM 3-methyladenine (3-MA) and 10.0 μM chloroquine (CQ) alone or in combination for 12 h (CQ for the last 4 h). Under Mo and Cd co-stress, data evidenced that YVAD addition decreased the number of autophagosomes, LC3 puncta, and AMPKα-1, Atg5, Beclin-1, LC3A, LC3B mRNA levels and LC3-II/LC3-I, Beclin-1 protein levels, and increased p62 expression levels. Besides, both 3-MA and CQ addition increased NLRP3, Caspase-1, NEK7, ASC, GSDMA, GSDME, IL-1β, IL-18 mRNA levels, NLRP3, Caspase-1 p20, ASC, GSDMD protein and ROS levels, and NO, LDH, IL-1β, IL-18 releases. Collectively, our results revealed that pyroptosis and autophagy co-induced by Mo and Cd were interrelated in duck renal tubular epithelial cells, and inhibiting pyroptosis might attenuate Mo and Cd co-induced autophagy, but inhibiting autophagy might promote Mo and Cd co-induced pyroptosis.
研究领域:
细胞生物学
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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
Antioxidants
·
2026
·Vol. 15
·期 5
·649
·
IF 8.2
Jue Yang,Peng Zhao,Lianghong Zhou,Hui Song,Zili Feng,Hongjian Cui,Yanmei Li,Jianfei Qiu,Xiaojiang Hao
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options, underscoring the urgent need for novel treatment strategies. Feilike (FLK), a Traditional Chinese Medicine formula with heat-clearing and detoxifying properties, aligns with key pathological features implicated in breast cancer progression. In addition, several of its components have demonstrated anti-tumor activity, positioning FLK as a potential therapeutic candidate for TNBC. In this study, we employed an integrated approach combining network pharmacology, transcriptomic analysis, and experimental validation to investigate the anti-TNBC effects of FLK. Our results demonstrate that FLK significantly inhibits the proliferation of TNBC cell lines and patient-derived organoids and induces typical pyroptotic features, including cell swelling and increased lactate dehydrogenase (LDH) release. Mechanistically, FLK triggers a mutant p53 signaling cascade involving calcium dysregulation, endoplasmic reticulum stress (ERS) activation, mitochondrial dysfunction, and reactive oxygen species (ROS) accumulation, which collectively activate the P38/JNK–Caspase-3/GSDME pathway to induce pyroptosis. In vivo, FLK markedly suppresses tumor growth in a 4T1 orthotopic mouse model and enhances the anti-tumor efficacy of Cyclophosphamide. Furthermore, Licochalcone B (LCB) is identified as a key bioactive constituent that recapitulates the pyroptosis-inducing effects of FLK. Collectively, our findings uncover a previously unrecognized mutant p53–ERS–ROS–MAPK signaling axis underlying FLK-induced pyroptosis and provide mechanistic insight and experimental evidence supporting the repurposing of FLK as a potential therapeutic strategy for TNBC.
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高影响因子
Cell Metabolism
·
2020
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IF 21.567
Wanfeng Xu,Yuan Che,Quan Zhang,Hai Huang,Chujie Ding,Yun Wang,Guangji Wang,Lijuan Cao,Haiping Hao
Summary Caspase-4 is an intracellular sensor for cytosolic bacterial lipopolysaccharide (LPS) and underlies infection-elicited pyroptosis. It is unclear whether and how caspase-4 detects host-derived factors to trigger pyroptosis. Here we show that mitochondrial permeability transition (MPT) activates caspase-4 by promoting the assembly of a protein complex, which we term the Apaf-1 pyroptosome, for the execution of facilitated pyroptosis. MPT, when induced by bile acids, calcium overload, or an adenine nucleotide translocator 1 (ANT1) activator, triggers assembly of the pyroptosome comprised of Apaf-1 and caspase-4 with a stoichiometry ratio of 7:2. Unlike the direct cleavage of gasdermin D (GSDMD) by caspase-4 upon LPS ligation, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby GSDME to induce pyroptosis. Caspase-4-initiated and GSDME-executed pyroptosis underlies cholestatic liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed light on understanding how cells execute intrinsic pyroptosis under sterile conditions.
研究领域:
免疫学
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细胞生物学
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分子生物学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-23
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IF 12.6
Zou Lan,Wang Rujing,Zhao Mengnan,Li Yuke,Sun Chen,Xie Jinjin,Chen Yan,Jing Qian,Mi Dandan,Shi Sanjun
Pyroptosis, a recently identified cellular demise regulated by gasdermin family proteins, is emerging as a promising avenue in cancer immunotherapy. However, the realm of light-controlled pyroptosis in cancer cells remains largely unexplored. In this study, we took a deliberate approach devoid of any chemical alterations to develop a novel photosensitizer called “pharmaceutical-dots (pharm-dots)” by combining nonemissive polymers (Poly (lactic-co-glycolic acid), PLGA) with nonfluorescent invisible molecules like curcumin, berberine, oridonin into PLGA nanoparticles (PLGA-NPs). Initially, our research commenced with a comprehensive mechanistic comparison study, consolidating fragmented information on optical mechanisms. This exploration revealed that surface passivation atoms play a dominant role in governing the fluorescence emission of PLGA-NPs. Remarkably, these new luminophores, composed of two non-inherently luminous components, exhibit a remarkable synergistic boost in photoluminescence through a “0 + 0 > 2” phenomenon. In-depth investigations uncovered that these luminous PLGA-NPs, capable of generating 1 O 2 , induce pyroptosis under photoexcitation conditions through the caspase-3/gasdermin E (GSDME) pathway. Simultaneously, our findings highlight PLGA-NPs as a novel optical formulation suitable for imaging, displaying substantial biological activity when paired with photoirradiation. This discovery holds the potential to facilitate the application of light-controlled pyroptosis in antitumor therapy, marking a promising stride toward innovative approaches in cancer treatment. Graphical abstract
研究领域:
癌症研究
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生物光子学
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纳米技术
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免疫疗法
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分子生物学
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PubMed
高影响因子
Biomaterials Science
·
2023
·
IF 6.6
Weichu Zhu,Jian Xu,Xianxian Yao,Shuting Mai,Dan Shu,Wuli Yang
Pyroptosis is a proinflammatory form of cell death mediated by members of the gasdermin family, and is a powerful tool against cancer. Herein, a pH-responsive doxorubicin (DOX)-encapsulating zeolitic imidazolate framework-8 (ZIF-8) nanoparticle coated with a carboxybetaine-based zwitterionic polymer (DOX@ZIF-8@PCBMA) was prepared. Furthermore, decitabine (DAC) was loaded to obtain a pyroptosis nanotuner (DOX@ZIF-8@PCBMA-DAC). This nanotuner displayed extended blood circulation and enhanced tumor accumulation. In addition, the ZIF-8 structure and disulfide-crosslinked PCBMA coating endowed DOX@ZIF-8@PCBMA-DAC with acidic-pH- and glutathione-responsive degradation. The nanotuner could robustly activate caspase-3 to induce gasdermin E (GSDME)-dependent pyroptosis via the sustained release of DAC and DOX, contributing to excellent tumor suppression with negligible side effects, which may provide novel insights into traditional chemotherapy.
研究领域:
纳米技术
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药学
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癌症治疗
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生物医学工程
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DOI
PubMed
高影响因子
Science Advances
·
2022
·Vol. 8
·期 46
·
IF 14.957
Zhanwei Zhou,Ruoxi Yang,Jingwen Dong,Yongxiang Di,Ying Yang,Ying Huang,Xue Yang,Wei Liu,Jinqiang Wang,Peifeng Liu,Zhen Gu,Minjie Sun
Directly delivering therapeutic proteins to their intracellular targets remains a great challenge. Here, we apply CD8+ T cells to form pores on the tumor cells’ plasma membranes, enabling perfusion of ribonuclease A (RNase A) and granzyme B into cells, therefore effectively inducing tumor apoptosis and pyroptosis by activating caspase 3 and gasdermin E pathways to potentiate the CD8+ T cell–mediated immunotherapy. Then, RNase A, programmed cell death ligand 1 antibody, and a photothermal agent were further loaded into an injectable hydrogel to treat the low immunogenic murine breast cancer. Notably, three courses of laser irradiation induced efficient cell apoptosis and immune activation, resulting in a notable therapeutic efficacy that 75% of the tumors were ablated without relapse.
研究领域:
癌症免疫治疗
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蛋白质递送
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细胞生物学
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免疫学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
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