Journal of Translational Medicine
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2026
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IF 9.7
Fei Zou,Zengrong Wu,Su Wang,Mengmeng Xu,Pianpian Xia,Yaxian Hu,Tang Fang,Peijun Hu,Chongyang Huang,Feihong Deng
Background Intestinal barrier defects cause antigen translocation and immune dysregulation. The pyroptosis of colonic epithelial cells (CECs) disrupts the colonic barrier, and its inhibition might be a therapeutic approach for ulcerative colitis (UC), but the mechanisms are not fully understood. Methods A DSS-induced UC model was established to assess the level of colonic epithelial cell pyroptosis. 16S rDNA sequencing and LC‒MS/MS were applied to screen potential candidate bacterial species and metabolites. The roles of target metabolites were evaluated in vivo using GSDMD-knockout mice. FHC cells treated with LPS + ATP were used as a cellular model of pyroptosis, and the underlying molecular mechanism was explored mainly by siRNA transfection and lentivirus infection. Results We found that DSS-treated mice exhibited increased levels of pyroptosis in the colon. Fecal microbiota transplantation (FMT) significantly suppressed mucosal inflammation and CEC pyroptosis, accompanied by increased levels of butyrate-producing bacteria and butyrate in feces. Butyrate treatment alleviated DSS-induced colitis in mice. Moreover, GSDMD knockout mitigated DSS-induced colitis in mice, whereas a butyrate intervention failed to further ameliorate colitis in GSDMD-knockout mice. Mechanistically, we found that butyrate significantly inhibited LPS + ATP-induced pyroptosis by activating its receptor, aryl hydrocarbon receptor (AhR), in FHC cells, while silencing AhR suppressed this effect. The overexpression of cGAS in FHC increased the level of pyroptosis, whereas the administration of butyrate inhibited the activation of the cGAS–STING pathway. Treatment with a cGAS inhibitor significantly reversed the increase in pyroptosis caused by AhR knockdown in pyroptotic FHC cells. Conclusions Gut microbiota-derived butyrate levels were increased after FMT. Butyrate suppressed the proinflammatory cGAS–STING–NF-κB signaling axis via AhR to inhibit CEC pyroptosis and thereby alleviate UC. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-026-08264-1.
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Frontiers in Pharmacology
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2026
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IF 5.4
Zhao-Lei Ding,Yi-Chen Ma,Chuan-Mei Liu,Xiu Lu,Rong-Rong Wang,Min-Min Tang,Dong-Xu Hua,Ling Zheng,Hui Zhao,Lin Fu
Background 1-Nitropyrene (1-NP) is harmful to the respiratory system and can evoke acute lung injury (ALI). Pyroptosis and apoptosis, two important types of programmed cell death, are involved in the pathological process of ALI. However, the roles and mechanisms of pyroptosis and apoptosis on 1-NP-incurred ALI remain unclear. Methods All the mice were exposed to a single dose of 1-NP (20 μg/mouse, dissolved in saline) or normal saline via intratracheal instillation. At different times after 1-NP exposure, the mice were sacrificed. Mouse lung epithelial (MLE-12) cells were incubated with 1-NP (5 μM), the indicators of pyroptosis and apoptosis were detected. Results Pulmonary pathological injury and inflammatory cell infiltration was observed in 1-NP-exposed mice. Additionally, the indicators of apoptosis, Bcl-2 was downregulated, Bad and Caspase-3, and apoptotic cells were increased in 1-NP-exposed mouse lungs and mouse lung epithelial (MLE-12) cells. Meanwhile, the proteins of GSDMD and Pro- and Cleaved Caspase-11 and the mRNAs of Il-1β and Il-18 , which are markers of pyroptosis, were increased after 1-NP treatment. Moreover, pretreatment with wedelolactone (WED), an antagonist of Caspase-11, alleviated 1-NP-induced ALI. As expected, pharmacological inhibition or genetic deletion of Caspase-11 abolished 1-NP-induced apoptosis and pyroptosis. Interestingly, 1-NP attenuated Caspase-11 proteasome degradation. Mechanistically, 1-NP downregulated the expression of SYVN1, an E3 ubiquitin ligase of Caspase-11. 1-NP promoted the interaction between SYVN1 and Caspase-11 and inhibited Caspase-11 ubiquitination and subsequent proteasome degradation. Transfection with SYVN1 overexpression plasmids abolished 1-NP-mediated the reduction of Caspase-11 ubiquitination-dependent degradation, apoptosis, and pyroptosis. Conclusions These results revealed that acute 1-NP may induce ALI via Caspase-11-mediated apoptosis and pyroptosis by downregulating SYVN1.
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Cell Death Discovery
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2026
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IF 10.4
Tian Zi-Chen,Liu Yang,Niu Yi-Jun,Ai Xin,Lao Su-Ya,Xu Wei-Ming,Lin Xiao-Tong,Xia Cheng-Jie,Cai Zhi-Xuan,Zhu Hai-Yan,Shi Xun-Long
Co-infection with influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) often causes severe pneumonia clinically; however, the role of innate immunity in this setting remains poorly understood. In our study, we established a murine co-infection model using low-lethality IAV and MRSA. Compared with single IAV or MRSA infection, co-infection with relatively low-lethality IAV and MRSA resulted in more severe pneumonia. Transcriptomic analysis indicated marked upregulation of genes involved in the pyroptotic signaling pathway. Consistently, flow cytometry and immunofluorescence analyses revealed caspase-1 activation and colocalization of gasdermin D (GSDMD) with macrophages in the lung. The RAW264.7 macrophage cell line was used for in vitro validation. Co-infection significantly enhanced the cleavage of caspase-1 and GSDMD in RAW264.7 cells. Furthermore, disulfiram, a pyroptosis inhibitor, was incorporated into the antiviral and antibacterial combination treatment. Although combined oseltamivir and linezolid treatment failed to fully alleviate lung injury, the inclusion of disulfiram, a GSDMD pore formation inhibitor, significantly ameliorated pneumonia symptoms and reduced inflammatory responses. Collectively, our findings highlight that macrophage pyroptosis contributes to the exacerbation of pneumonia induced by IAV and secondary MRSA co-infection. Inhibition of GSDMD-mediated pyroptosis may represent a viable therapeutic approach to alleviate disease severity and improve outcomes in lethal co-infection.
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POULTRY SCIENCE
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2026
·Vol. 105
·期 12
·107847
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IF 4.5
Shunxing Liu,Yanling Xiong,Zhentao Cheng,Anchun Cheng,Rutao Lin,Hui Li,Yao Huang,Binlan Zhou,Ting Yang,Chunlan Shan
Mycoplasma gallisepticum ( MG ), a significant pathogen, causes chronic respiratory disease (CRD) in poultry, characterized by coughing, wheezing, and dyspnea. This widespread disease severely impedes the healthy development of the poultry industry. Hydroxytyrosol (HT), a plant-derived monomeric compound, possesses diverse bioactivities, including antibacterial, antioxidant, and cardiovascular protective properties. This study aimed to investigate HT's protective effect against MG -induced inflammatory damage in HD11 cells. The findings revealed that MG infection activated the TLR4/NF-κB signaling pathway and the NLRP3 inflammasome, resulting in macrophage accumulation and inflammatory damage in the lung tissue of chicks. HT mitigated MG -induced inflammatory damage in HD11 cells, inhibited the M1 phenotype shift, and reduced the secretion of pro-inflammatory factors. Molecular docking and molecular dynamics simulations demonstrated HT's stable, spontaneous binding to NLRP3. Further investigations showed that HT alleviates oxidative stress-induced cellular damage, diminishes pathological apoptosis and pore formation, and concurrently reduces NLRP3 activation by regulating the TLR4/NF-κB pathway, thereby downregulating the expression of key pyroptosis factors. In summary, HT reduces NLRP3 inflammasome activation by specifically inhibiting the TLR4/NF-κB signaling axis, consequently alleviating inflammation-induced damage, oxidative stress, and pyroptosis in HD11 cells caused by MG infection.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2026
·Vol. 27
·期 11
·4777
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IF 5.6
Chunlu He,Yan Wang,Jialiang Lin,Zihao Yu,Yuan Shi,Jianhua Cheng,Yunyun Jiang,Litao Hu
As emerging global environmental contaminants, organic ultraviolet absorbers (OUVAs) are widely used in personal care formulations and exhibit environmental persistence and potential bioaccumulation. Among these compounds, 2-ethylhexyl salicylate (EHS) and homosalate (HMS) are the most frequently used salicylate-type UV filters in cosmetic formulations. Although an increasing number of studies have demonstrated their environmental hazards, little is known about the molecular mechanisms underlying their cytotoxicity in mammalian systems, a fundamental knowledge gap for both human health protection and the development of more environmentally friendly consumer goods. In this study, we used mouse embryonic fibroblasts (MEFs, 3T6) and zebrafish as models to assess the toxicological phenotypes of EHS and HMS in vitro and in vivo, respectively. We found that both EHS and HMS induced cellular damage characterized by oxidative stress, disrupted intracellular calcium homeostasis, mitochondrial impairment, and DNA damage. Importantly, molecular analyses further suggested the concurrent activation of two distinct regulated cell death programs: pyroptosis, as suggested byCaspase-11-mediated GSDMD cleavage, and necroptosis, as suggested byZBP1-RIPK3-Caspase-8-mediated MLKL phosphorylation. The in vitro data have been partially validated at the level of gene expression and in developmental toxicity in the zebrafish model, providing some in vivo phenotypic and molecular correlates. While the upstream events were experimentally verified, the causal links among them remain to be further elucidated. Taken together, this work suggested that OUVA-induced toxicity is not limited to isolated oxidative damage, but may also involve the activation of two different cell death programs. These findings provide important molecular clues to understanding the potential health and ecological risks of widely used UV filters and offer a scientific basis for their more environmentally friendly safety evaluation and regulatory management, which are crucial for advancing more sustainable chemistry and safer consumer goods.
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Thoracic Cancer
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2026
·Vol. 17
·期 17
·e70383
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IF 2.6
Kairui Zhu,Yulong Mu,Zhenguo Su,Zhen Yue,Dongyang Wu,Guiwu Qu,Chenyang Jiang,Qing Li,Youjie Li,Ning Xie
Background Pyroptosis-related signaling contributes to lung adenocarcinoma (LUAD) progression and prognosis. Apigenin (AP) has anti-inflammatory and cytoprotective properties, but its effects on pyroptosis-associated signaling in injured LUAD cells remain unclear. Methods A549 cells were treated with carbonyl cyanide m -chlorophenyl hydrazone (CCCP) and ferrous sulfate (FeSO 4 ) to establish a cellular injury model. Cell morphology, Cell Counting Kit-8 signals, and pyroptosis-associated proteins were assessed after AP treatment. Network pharmacology, molecular docking, molecular dynamics simulations, and analyses of The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to prioritize candidate targets, characterize pyroptosis-related genes, and develop a prognostic signature. Results CCCP/FeSO 4 reduced CCK-8 signals and induced morphological injury, whereas AP partially reversed these changes. AP also reduced alterations in GSDMD-N, caspase-1, IL-1β, TNF-α/NF-κB pathway proteins, AIM2, and ASC. TNF was prioritized as a candidate target, and computational analyses predicted a potentially stable AP–TNF interaction without demonstrating direct binding. Bioinformatic analyses identified distinct pyroptosis-related LUAD subgroups and generated a prognostic signature that stratified survival in training and external validation cohorts. AIM2 was additionally prioritized as a LUAD- and stress-associated candidate. Conclusion AP attenuated CCCP/FeSO 4 -induced injury and pyroptosis-associated molecular changes in A549 cells, potentially through TNF-α/NF-κB and AIM2-related signaling. Further mechanistic validation is required.
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CNS Neuroscience & Therapeutics
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2026
·Vol. 32
·期 7
·e71058
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IF 6.6
Chenglong Li,Xi Gou,Yingying Zhao,Lina Zhang,Shuai Liu,Shenhui Deng,Qi Li,Sihua Qi
Aims This study investigates whether histone H3K18 lactylation (H3K18la) contributes to perioperative neurocognitive disorders (PND) by upregulating immune checkpoint Lymphocyte activation gene 3 (Lag3) and microglial pyroptosis, thereby aggravating neuroinflammation in the hippocampus. Methods Lactate levels and H3K18la expression were measured in mouse hippocampus after surgery. H3K18la downstream targets were identified by CUT&Tag and RNA-seq. After Lag3 silencing in BV2 cells, downstream pathways were screened and validated by RNA-seq and in vitro assays. Glycolysis inhibitors and Lag3 antibody were used to assess cognitive function and pyroptosis-related protein expression in postoperative mice. Results Surgery significantly elevated hippocampal lactate and H3K18la levels in mice. Inhibiting glycolysis led to a reduction in H3K18la and mitigated cognitive impairments in the PND model mice. CUT&Tag and RNA-seq revealed that H3K18la transcriptionally activates Lag3 by enriching at its promoter, and Lag3 blockade improved postoperative cognition. Furthermore, Lag3 upregulation triggered microglial pyroptosis via NOD-like receptor protein 3 (NLRP3) signaling, thereby aggravating neuroinflammation and promoting PND. Conclusions Surgical trauma-induced increase of H3K18la in microglia promotes PND by upregulating Lag3 and triggering NLRP3-dependent microglial pyroptosis, highlighting the H3K18la–Lag3–NLRP3 axis as a therapeutic target for PND.
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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.
研究领域:
药理学
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风湿病学
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细胞生物学
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药物发现
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分子医学
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JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
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2025
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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.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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细胞死亡研究
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JOURNAL OF HAZARDOUS MATERIALS
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2025
·
IF 11.3
Jia-Gen Cui,Hao Zhang,Yue-Qi Zhang,Bing Sun,Xue-Nan Li,Yi Zhao,Jin-Long Li
The widespread use of di(2-ethylhexyl) phthalate (DEHP) as a plasticizer raises concerns due to its environmental persistence and cardiotoxicity. Nevertheless, the precise mechanisms through which DEHP induces cardiac damage, particularly concerning myocardial injury, remain inadequately understood. Using a mouse model, this investigation employed UPLC-MS/MS to demonstrate that exposure to DEHP significantly elevated the concentration of its primary metabolite, mono(2-ethylhexyl) phthalate (MEHP), in cardiac tissue, while DEHP itself did not exhibit a significant difference. DEHP-induced myocardial injury in mice was evidenced by disorganized myocardial fibers, collagen deposition and elevated serum creatine kinase-MB (CK-MB) and C-reactive protein (CRP). Further analysis through database screening and experimental validation indicated that DEHP mediates myocardial injury by activating the sphingolipid metabolic pathway involving the sphingosine kinases 1 (SPHK1)/ sphingosine 1-phosphate receptor 2 (S1PR2) axis. Molecular docking and cellular thermal shift assays (CETSA) confirmed that MEHP could directly bind to and enhance the stability of SPHK1. DEHP exposure also increased pyroptosis-related proteins, reversible via SPHK1 inhibitor PF543 or S1PR2 siRNA. In conclusion, this study first links DEHP-induced cardiac pyroptosis to SPHK1/S1PR2 signaling in mice, providing novel insights into DEHP-associated cardiotoxicity, contributing to cardiac damage and thereby offering new theoretical insights into DEHP-related cardiac toxicity.
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INFLAMMATION
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2026
·Vol. 49
·期 1
·41
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IF 5
Zheng-qing Hu,Ruijie Ma,Hang Zhang,Jiahao Miao,Jia-qing Sun,Jinlong Yuan,Jiaqiang Liu,Zihuan Zhang,Dayong Xia
This study aims to elucidate the mechanism by which Heat Shock Protein 60 (HSP60) mediates microglial pyroptosis in the context of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and to investigate the effects of HSP60 inhibition on EBI after SAH. A mouse subarachnoid hemorrhage (SAH) model was established using prechiasmatic cistern blood injection. In vitro, microglia were stimulated with 25 µmol/L oxyhemoglobin (OxyHB) to simulate the SAH pathological environment. In vivo, mice received 100 mg/kg Mizoribine, while in vitro, 80 µmol/L Mizoribine was used to suppress SAH-induced HSP60 upregulation. Techniques including Western blotting, immunofluorescence, immunohistochemistry, transmission electron microscopy, ELISA, modified Garcia neurological scoring, beam walking, brain water content measurement, Morris water maze, TUNEL staining, and Nissl staining were employed to systematically investigate the role of HSP60 inhibition in neuroinflammation and microglial pyroptosis after SAH. Compared to the sham group, both in vivo and in vitro studies with blinded, random sampling of six groups demonstrated a significant increase in HSP60 expression post-SAH. In vivo, 100 mg/kg Mizoribine alleviated blood-brain barrier disruption, cerebral edema, neuronal apoptosis/necrosis, and improved neurological deficits and cognitive impairment. In vitro, 80 µmol/L Mizoribine markedly attenuated microglial activation and pyroptosis, downregulated pro-inflammatory cytokines, and mitigated neuroinflammation. The upregulation of HSP60 after SAH promotes NLRP3 inflammasome assembly by activating the TLR4/MyD88/NF-κB signaling pathway, thereby inducing microglial pyroptosis and exacerbating the progression of early brain injury. Inhibition of HSP60 represents a potential therapeutic strategy for ameliorating EBI after SAH.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2026
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IF 9.7
Yehui Kang,Yahui Zhang,Weijiao Fan,Liya Yu,Mengdie Yu,Yuejia Ding,Yu Cai,Aihong Jiao,Jiajie Xu
Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy due to limited therapeutic options and considerable treatment-related toxicity. In this study, we present an innovative nanotherapeutic platform—monocarboxylate transporter 1 (MCT1) antibody-targeted nanoparticles co-loaded with a second near-infrared window (NIR-II, 1000–1700 nm) absorbing conjugated polymer (PDTP-TBZ-OD, denoted as PTO) and emodin (MCT@PTO-Em NPs) —that synergistically integrates emodin-induced pyroptosis with NIR-II mediated mild photothermal therapy (MPTT) to address critical limitations of current HNSCC treatments strategies. The synthesized NIR-II-absorbing conjugated polymer PTO exhibits strong absorption at 1064 nm and a high photothermal conversion efficiency (39 %), enabling deeptissue penetration and precise hyperthermia control. Accordingly, MCT@PTO-Em NPs implement a dual-modal therapeutic strategy that triggers pyroptosis through NLRP3 inflammasome activation while simultaneously enhancing tumor cell death via mild hyperthermia. Moreover, emodin encapsulated within the nanoparticles (NPs) inhibits heat-shock protein 70 (HSP70), thereby disrupting cellular thermoresistance mechanisms and sensitizing cancer cells to MPTT. Additionally, surface functionalization of the nanoparticles with MCT1-targeting antibodies enhances tumor-specific delivery and intracellular accumulation, thereby minimizing off-target effects. Both in vitro and in vivo studies demonstrate that MCT@PTO-Em NPs achieve superior tumor suppression through the synergistic interplay between pyroptosis and MPTT, while exhibiting excellent biocompatibility. This work presents a precision nanomedicine strategy that integrates molecular targeting, pyroptosis-mediated immune activation, and MPTT, offering a transformative therapeutic paradigm for HNSCC and other solid tumors.
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