INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Yang Zhang,Deguo Xing,Yi Liu,Shiyu Sha,Yueying Xiao,Zhonghao Liu,Qingfeng Yin,Zengxin Gao,Wenguang Liu
Intervertebral disc degeneration (IVDD) is a chronic degenerative disease with a complex pathophysiological mechanism. Increasing evidence suggests that the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of nucleus pulposus cells (NPCs) plays a crucial role in the pathological progression of IVDD. Pyroptosis is a novel form of programmed cell death characterized by the formation of plasma membrane pores by gasdermin family proteins, leading to cell swelling, membrane rupture, and the release of inflammatory cytokines, which trigger an inflammatory response. The close relationship between pyroptosis and mitophagy has been previously described in various diseases, but the crosstalk between pyroptosis and mitophagy in IVDD remains unexplored. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and homeostasis regulation and has been shown to promote lysosomal biogenesis and function. However, the potential role and underlying mechanisms of CREG1 in the progression of IVDD have not yet been reported. In this study, we first observed that CREG1 is downregulated following IVDD and that pyroptosis occurs. Furthermore, CREG1 knockdown inhibited NPC proliferation and exacerbated apoptosis and degeneration. Moreover, we confirmed that CREG1 knockdown induced NLRP3 activation while also leading to mitophagy inhibition and mitochondrial dysfunction in NPCs. CREG1 overexpression ameliorated LPS-induced mitophagy inhibition and mitochondrial dysfunction by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. However, these protective effects were reversed by pretreatment with the mitophagy inhibitor cyclosporin A (CsA). In a rat model of IVDD, imaging and histological assessments revealed that CREG1 overexpression effectively alleviated the progression of IVDD. Additionally, CREG1 overexpression reduced the expression of NLRP3, caspase-1, and IL-1β while increasing the expression of collagen II, PINK1 and LC3, delaying the course of IVDD. Overall, this study highlights the importance of the interplay between CREG1-mediated regulation of mitophagy and pyroptosis in the pathogenesis of IVDD, identifying CREG1 as a promising therapeutic target for IVDD treatment.
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AMERICAN JOURNAL OF CHINESE MEDICINE
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2025
·Vol. 53
·期 02
·475-499
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IF 5.5
Bing Li,Shuanglong Mou,Chenrui Zhang,Tingting Zhu,Xingwei Hu,Mengsha Li
Myocardial infarction (MI) is a significant threat to human health worldwide. Following MI, cardiomyocytes (CMs) undergo pyroptosis, exacerbating the damage caused by infarction. Ginseng may play a role in alleviating CM pyroptosis. However, further exploration is needed regarding its main active ingredients and effects. By employing network pharmacology on the active ingredients of ginseng, MI and pyroptosis, and employing molecular docking between such ingredients and pyroptosis-related proteins, we screened for the main ingredient of ginseng. Through network pharmacology and molecular docking, we identified ginsenoside Rh2, which acts on MI and cell pyroptosis, as the most likely active ingredient that stably binds to pyroptosis-related proteins. We subsequently constructed a neonatal rat CM oxygen–glucose deprivation (OGD) model in vitro and an MI mouse model in vivo . Ginsenoside Rh2 was administered, with losartan used as a positive control. In the in vitro OGD model, ginsenoside Rh2 increased the viability of primary rat CMs and mitigated OGD-induced pyroptosis. In the in vivo MI model, ginsenoside Rh2 reduced CM pyroptosis, decreased infarct size, and subsequently improved cardiac function. Our study provides a novel therapeutic strategy for MI by attenuating CM pyroptosis.
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ACS Applied Materials & Interfaces
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2024
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IF 8.3
Zhun Li,Zhenxing Zhu,Dongtao Zhou,Yusheng Chen,Yi Yin,Zhibin Zhang,Jingjing Yang,Yanfeng Gao,Weiming Zhu,Yujun Song,Yi Li
Crohn’s disease (CD) is a refractory chronic inflammatory bowel disease (IBD) with unknown etiology. Transmural inflammation, involving the intestine and mesentery, represents a characteristic pathological feature of CD and serves as a critical contributor to its intractability. Here, this study describes an oral pyroptosis nanoinhibitor loaded with tumor necrosis factor-α (TNF-α) deoxyribozymes (DNAzymes) (DNAzymes@degradable silicon nanoparticles@Mannose, Dz@MDSN), which can target macrophages at the site of inflammation and respond to reactive oxygen species (ROS) to release drugs. Dz@MDSN can not only break the inflammatory cycle in macrophages by degrading TNF-α mRNA but also reduce the production of ROS mainly from macrophages. Moreover, Dz@MDSN inhibits excessive pyroptosis in epithelial cells through ROS clearance, thereby repairing the intestinal barrier and reducing the translocation of intestinal bacteria to the mesentery. Consequently, these combined actions synergistically contribute to the suppression of inflammation within both the intestine and the mesentery. This study likely represents the first successful attempt in the field of utilizing nanomaterials to achieve transmural healing for CD, which also provides a promising treatment strategy for CD patients.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-23
·
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
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JOURNAL OF MEDICINAL CHEMISTRY
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2025
·
IF 6.8
Wei Wu,Jiaen Huang,Yuling Li,Jiaxi Chen,Xiaowei Kuang,Manzhen Ye,Rui Chen,Junli An,Zunnan Huang,Jing Sun
Cancer immunotherapy has revolutionized oncology by leveraging host immunity to eliminate malignant cells. In this study, five iridium(III) complexes (Ir1–Ir5) were synthesized and evaluated for their in vitro antitumor activity against various tumor cell lines. Among these, Ir4 and Ir5 exhibited the highest cytotoxicity and the most rapid cellular uptake in MDA-MB-231 cells. Colocalization experiments confirmed their accumulation in the endoplasmic reticulum (ER) and their ability to induce pyroptosis. Additionally, both complexes triggered ER stress, leading to increased calreticulin exposure on the cell surface, high-mobility group box 1 secretion, and ATP release, which collectively promoted immunogenic cell death. In vivo, a triple-dose Ir4 vaccine regimen significantly suppressed tumor growth compared to other treatment groups. These findings highlight the potential of Ir4-based novel triple-dose vaccination as a promising cancer immunotherapy strategy.
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ENVIRONMENT INTERNATIONAL
·
2024
·
IF 10.3
Bingli Zhang,Yizhou Zhong,Jiaxin Du,Rongyi Ye,Bingchi Fan,Yanhong Deng,Ruobing Bai,Yu Feng,Xiaohong Yang,Yuji Huang,Boxuan Liang,Jiewei Zheng,Weifeng Rong,Xingfen Yang,Zhenlie Huang
1,2-Dichloroethane (1,2-DCE) is a prevalent environmental contaminant, and our study revealed its induction of testicular toxicity in mice upon subacute exposure. Melatonin, a prominent secretory product of the pineal gland, has been shown to offer protection against pyroptosis in male reproductive toxicity. However, the exact mechanism underlying 1,2-DCE-induced testicular toxicity and the comprehensive extent of melatonin's protective effects in this regard remain largely unexplored. Therefore, we sequenced testis piRNAs in mice exposed to environmentally relevant concentrations of 1,2-DCE by 28-day dynamic inhalation, and investigated the role of key piRNAs using GC-2 spd cells. Our results showed that 1,2-DCE induced mouse testicular damage and GC-2 spd cell pyroptosis. 1,2-DCE upregulated the expression of pyroptosis-correlated proteins in both mouse testes and GC-2 spd cells. 1,2-DCE exposure caused pore formation on cellular membranes and lactate dehydrogenase leakage in GC-2 spd cells. Additionally, we identified three upregulated piRNAs in 1,2-DCE-exposed mouse testes, among which piR-mmu-1019957 induced pyroptosis in GC-2 spd cells, and its inhibition alleviated 1,2-DCE-induced pyroptosis. PiR-mmu-1019957 mimic and 1,2-DCE treatment activated the expression of interferon regulatory factor 7 (IRF7) in GC-2 spd cells. IRF7 knockdown reversed 1,2-DCE-induced cellular pyroptosis, and overexpression of piR-mmu-1019957 did not promote pyroptosis when IRF7 was inhibited. Notably, melatonin reversed 1,2-DCE-caused testicular toxicity, cellular pyroptosis, and upregulated piR-mmu-1019957 and IRF7. Collectively, our findings indicated that melatonin mitigates this effect, suggesting its potential as a therapeutic intervention against 1,2-DCE-induced male reproductive toxicity in clinical practice.
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Scientific Reports
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2025
·Vol. 15
·期 1
·1-12
·
IF 3.9
Tu Sha,Jing Xi,Bu Xiaoling,Zhang Qingfang,Liao Shanying,Zhu Xiaobo,Guo Ying,Sha Weihong
Despite advances in research, studies on predictive models for Non-Alcoholic Fatty Liver Disease (NAFLD)-related fibrosis remain limited. Identifying new biomarkers to distinguish Non-Alcoholic Steatohepatitis (NASH) from NAFLD would aid in the treatment of NASH. Gene expression and clinical profiles of NAFL and NASH patients were collected from databases. Differentially expressed genes with prognostic value were used to construct predictive model. Validation of fibrosis stage-related pyroptosis-related genes (PRGs) was performed using Sprague-Dawley rats liver fibrosis models induced by CCl4 or PS. Immune cell infiltration assessment demonstrated that stromal score, immune score, and ESTIMATE score were higher in patients with NASH compared to those with NAFL. BAX , BAK1 , PYCARD , and NLRP3 were identified as hub genes that exhibit a strong correlation with fibrosis stage. Additionally, the expression of these genes was increased in fibrotic liver tissues induced by CCl4 and PS. The pyroptosis-associated gene signature effectively predicts the degree of liver fibrosis in NASH patients. Our study indicates that BAX , BAK1 , PYCARD , and NLRP3 might serve as biomarkers for NASH-associated fibrosis.
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JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
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2025
·
IF 2.5
Yu Pan,Rui Li,Huanhuan Ma,Xiaolei Hu,Jun Zhao,Juanjuan Qiao,Xiyao Dou,Yanan Wang,Yanzhi Zhang,Xiuli Wang,Lin Wang
Expression of the critical pyroptosis protein gasdermin E (GSDME) has been reported to be regulated by DNA methylation and negatively correlated with expression of estrogen receptor (ER) in breast cancer tissues, suggesting that estrogen-induced target gene methylation may be involved in the regulation of GSDME expression in breast cancer cells. To test this hypothesis, we treated MCF-7 and T47D ER-positive breast cancer cells with 17-β-estradiol (E 2 ), either alone or in combination with selective ERα antagonist AZD9496, selective ERβ antagonist PHTPP, DNA methyltransferase (DNMT) inhibitor RG108, and selective ER degrader Fulvestrant (Ful). Then, GSDME protein and mRNA expression were examined with western blot and RT-qPCR. Pyroptosis was induced by short-wave ultraviolet (UV-C) and detected with morphological observation, lactate dehydrogenase (LDH) release assay, and propidium iodide-Annexin V-FITC fluorescence staining. The methylation status of the GSDME promoter was tested with methylation-specific PCR. The results demonstrated that 100 nM E 2 significantly decreased GSDME protein and mRNA expression in MCF-7 and T47D cells, and significantly inhibited UV-C-induced pyroptosis. AZD9496 but not PHTPP significantly attenuated the down-regulatory effect of E 2 on GSDME expression. E 2 induced DNA methylation in the GSDME promoter region and up-regulated DNMT1 expression. RG108 strengthened UV-C-induced pyroptosis, and Ful reversed the inhibitory effects of E 2 on UV-C-induced pyroptosis of MCF-7 and T47D cells . Taken together, our study suggests that E 2 down-regulated GSDME expression in ERα-positive breast cancer by promoting GSDME promoter methylation, and inhibited UV-C-induced pyroptosis.
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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.
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Journal of Advanced Research
·
2025
·
IF 13
Hanwen Zhang,Tanxin Yu,Nanfang Zhuo,Zongxin Zhu,Shihan Lin,Shiying Zhao,Huilin Yu,Youli Zhang,Aimin Wu,Jiangning Wang,Yifei Zhou,Xiaolei Zhang
Introduction Osteoarthritis (OA), a leading cause of joint dysfunction, is characterized by progressive cartilage degradation linked to chondrocyte pyroptosis, yet disease-modifying therapies remain elusive. In this study, we conducted the first systematic drug repurposing screen in chondrocytes, aiming at identifying drugs that may suppress pyroptosis and verifying the therapeutic effects on OA. Methods Mitiglinide’s effects on chondrocyte viability were quantified via CCK-8 assays and live/dead staining. Pyroptosis inhibition, extracellular matrix (ECM) homeostasis, and NF-κB activation were measured by western blot and immunofluorescence. Network pharmacology analysis and molecular docking were applied to predict the interacting protein of mitiglinide, while Nrf2 was knocked down by siRNAs to confirm its role in mitiglinide regulated pyroptosis and ECM. In vivo , destabilization of the medial meniscus (DMM) model −induced OA mice received mitiglinide for 8 weeks, with efficacy evaluated through X-ray, OARSI-graded histopathology, immunohistochemistry, Hematoxylin-Eosin and Safranin O-Fast green staining. Results Through high-throughput screening (HTS) of 1,228 FDA-approved drugs, we identified a list of pyroptosis inhibitors, and mitiglinide was suggested as one of the most potent pyroptosis inhibitors in chondrocyte. Mechanistic studies demonstrated that mitiglinide may directly target Nrf2 and suppress its downstream NF-κB-driven NLRP3 inflammasome activation; it may also promote ECM homeostasis in chondrocytes. In vivo study showed that mitiglinide may effectively attenuate OA pathology in mice. Conclusion Mitiglinide, identified via FDA-drug-library screening, alleviates OA progression by suppressing NLRP3 inflammasome activation and ECM degradation via activation of the Nrf2/HO-1 signaling pathway. This positions mitiglinide as a repurposed disease-modifying OA drug candidate.
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Frontiers in Immunology
·
2025
·
IF 5.9
You Zhou,Kai Yang,Jian Wang,Ruijuan Guan,Wei Liu,Chaowei Wen,Liang Yuan,Tiange Zhang,Wei Feng,Yuanyuan Li,Jingyi Xu,Wenju Lu
Backgrounds: Exposure to fine particulate matter (PM2.5) triggers airway inflammation through the activation of the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway, contributing to the pathogenesis of various acute and chronic respiratory diseases. Mucin 1 (MUC1), a transmembrane glycoprotein highly expressed on airway epithelial cells, is known to modulate TLR-mediated inflammatory responses. However, the specific role and molecular mechanism by which MUC1 regulates PM2.5-induced airway inflammation remain inadequately understood.Methods: Lung injury models were established using Muc1+/+ and Muc1-/- rats via intranasal instillation of PM2.5. Histopathological changes and inflammatory responses were evaluated following treatment. In parallel, human bronchial epithelial cells (16HBE) were transfected with MUC1 overexpression and knockdown plasmids, along with corresponding controls. An IRAK4-specific inhibitor was employed to explore the mechanistic role of MUC1 in regulating the TLR4/IRAK4/NF-κB signaling cascade and associated pyroptosis.Results: PM2.5 exposure caused notable epithelial disruption, inflammatory infiltration, and submucosal fibrosis in Muc1-/- rats compared to Muc1+/+ controls. While TLR4 expression was not significantly altered, NF-κB and NLRP3 inflammasome activity were markedly elevated in Muc1-deficient rats. In 16HBE cells, MUC1 overexpression attenuated, whereas MUC1 knockdown exacerbated, PM2.5-induced activation of the IRAK4/NF-κB signaling axis and pyroptosis-related markers (IL-1β, IL-18, NLRP3, GSDMD). Furthermore, pharmacological inhibition of IRAK4 mitigated these effects, confirming the involvement of the IRAK4 pathway in MUC1-mediated protection.Conclusions: MUC1 is upregulated in airway epithelial cells upon PM2.5 exposure and serves as a key endogenous inhibitor of airway inflammation. It exerts its anti-inflammatory and anti-pyroptotic effects by suppressing IRAK4 phosphorylation, thereby modulating downstream NF-κB/NLRP3/GSDMD signaling. These findings highlight MUC1 as a potential therapeutic target for PM2.5-induced airway inflammatory diseases.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Gao He,Ziyu Feng,Xinghai Liu,Muyu Zhu,Xiaoan Liu,Lile Dong,Xiafei Yu
HB@T nanosheets generate sustained ROS under ultrasound activation, inducing redox collapse and mitochondrial damage. • ROS-mediated mitochondrial injury activates the canonical NLRP3/caspase-1/GSDMD pathway and triggers pyroptotic cell death. • HB@T-induced pyroptosis promotes CRT release, DC maturation, and systemic antitumor immunity with abscopal effects. Triple-negative breast cancer (TNBC) remains one of the most treatment-refractory malignancies, largely attributable to its profoundly immunosuppressive microenvironment that enables tumor immune evasion. Pyroptosis, a gasdermin-mediated lytic cell death pathway, holds promise for reinvigorating antitumor immunity through the release of immunostimulatory signals. However, the clinical translation of pyroptosis-based therapy is hindered by the lack of spatiotemporally controllable triggers and the robust glutathione (GSH)-centered antioxidant defense inherent to TNBC cells. Herein, a defect-engineered core-shell Bi 4 TaO 8 Br@TaO X (HB@T) piezoelectric nanosheet is developed as an ultrasound (US)-responsive platform to circumvent these barriers. Structurally, HB@T comprises a crystalline Bi₄TaO₈Br core that ensures stable charge generation, surrounded by an oxygen-vacancy-rich amorphous Ta-based oxide shell that facilitates oxygen pre-adsorption and GSH consumption. This rational design yields a narrowed bandgap of 2.36 eV and an elevated piezoelectric coefficient (d33 = 24.1 pm V −1 ), enabling efficient electron-hole separation and robust reactive oxygen species (ROS) production under US stimulation. The dual functionality of sustained ROS generation coupled with active GSH depletion synergistically disrupts redox homeostasis in tumor cells, thereby triggering the NLRP3/caspase-1/GSDMD pyroptotic cascade. This process elicits profound immunogenic responses, including dendritic cell maturation, CD8 + T cell infiltration, and expansion of effector memory (T EM ) and central memory (T CM ) T cell populations. Remarkably, in a bilateral tumor model, HB@T treatment achieves 71% inhibition of primary tumors and 67% suppression of distant untreated lesions, demonstrating a potent abscopal effect indicative of systemic immune reactivation. Collectively, this work establishes an innovative therapeutic paradigm that integrates US-activated piezoelectric catalysis with pyroptosis-driven immunomodulation, offering a clinically translatable strategy to overcome immune tolerance in TNBC. Defect-engineered core-shell HB@T piezoelectric nanosheet is developed as an US-responsive platform to induce pyroptosis and elicit systemic abscopal antitumor immunity. The dual functionality of ROS generation coupled with GSH depletion synergistically disrupts redox homeostasis, triggering the NLRP3/caspase-1/GSDMD pyroptotic cascade. Remarkably, HB@T treatment achieves 71% inhibition of primary tumors and 67% suppression of distant untreated lesions, demonstrating a potent abscopal effect indicative of systemic immune reactivation. Download: Download high-res image (128KB) Download: Download full-size image
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