Pyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in vitro.

A murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte pyroptosis.

Knockdown of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1β), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1β protein reversed the inhibitory effect of Caspase-1 knockdown on pyroptosis.

Overall, activating the Caspase-1/IL-1β axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.

Sepsis is a life-threatening condition characterized by multiple organ dysfunction syndrome resulted from dysregulated host responses to infection. Sepsis-associated encephalopathy (SAE) is one of the most common symptoms of acute-phase sepsis, with nearly 70 % of patients with sepsis ultimately developing SAE. Pyroptosis represents a type of cell death that is initiated by inflammation. This cell death type is associated with various infectious and noninfectious diseases. The gasdermin family proteins are crucial cell death executors and critical components in regulating the canonical pyroptosis pathway in microglia. In this review, we summarize the inhibitory effects of several drugs and genes on the pyroptosis pathway. Our findings suggest that several drugs (puerarin, VX765, HC067047, dexpramipexole, and Danhong injection), erbin gene, and TRIM45 knockdown improve SAE by suppressing the canonical pathway of NLRP3/caspase-1/gasdermin D-mediated pyroptosis. Therefore, they have significant importance in terms of brain protection. Moreover, we review the relevant literature published in recent years and summarize the research status and development prospects in this field to provide a basis for subsequent related research.

Major depressive disorder is one of the most common psychiatric disorders, and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in depression. Dorsal raphe nucleus (DRN), as the main origin of producing serotonin in the brain, is an important functional brain region in depressive disorders. However, the relationship between NLRP3 in the DRN and depression has not been clarified in previous studies. So, we focus on demonstrating the role of NLRP3 expressed in DRN in depression. In this study, the male C57BL/6 J mice were exposed to chronic unpredictable mild stimulation and the expression and cellular localization of NLRP3 in DRN were analyzed. Subsequently, the mice were treated with the NLRP3 inhibitor MCC950 to inhibit NLRP3 inflammasome, and the expression of NLRP3 was knocked down in certain cells within the DRN of NLRP3fl/fl mice to investigate the role of NLRP3 in regulating depressive phenotype. Compared with the control group, the expression of NLRP3 in DRN of CUMS group was significantly increased, especially in the microglia and neuron. Furthermore, treatment with the NLRP3 inhibitor induced a significant antidepressant effect, and the depressive phenotype of NLRP3fl/fl mice was rescued after knocking down NLRP3 in the microglia or neuron. In addition, the expression levels of related molecules in the NLRP3 inflammasome pathway were significantly higher in the CUMS group compared to the control group. These results illustrated that NLRP3 played an important role in regulating depressive phenotype in DRN, and suggested a new therapy target for depression.

Atrophic gastritis (AG) is a chronic inflammation where gastric glandular cells are replaced by intestinal-type epithelium. Gastric epithelial cell loss is often linked to multiple cell death signaling pathways. While Helicobacter pylori (H. pylori) infection is the main cause of AG, its role in inducing cell death goes beyond apoptosis and autophagy. Pyroptosis could promote development of inflammation related cancers, but its involvement in H. pylori-induced malignant transformation remains unclear.

The enrichment of pyroptosis signaling across pathological stages was assessed using immunohistochemistry and bioinformatic analysis. Gastric epithelial cells were co-cultured with VacA recombinant protein or VacA+H. pylori to investigate the role of VacA in pyroptosis, and its downstream targets. TNFAIP3 or TRAF1 was silenced/overexpressed in gastric epithelial cells to explore their impact on pyroptosis. Finally, the interaction between TNFAIP3 and TRAF1 was examined using Western Blot, immunofluorescence, co-immunoprecipitation and ubiquitin assays.

Expression of pyroptosis components and pyroptosis enrichment score were upregulated in AG and gastric cancer tissues compared to normal or non-atrophic gastritis tissues. Upon incubation with VacA recombinant protein or VacA+H. pylori, pyroptosis and TNFAIP3/TRAF1 were elevated in gastric epithelial cells. TRAF1 promoted expression of downstream pyroptosis components and release of IL-1β/IL18. TRAF1 ablation could reverse pyroptosis activation caused by VacA. Finally, we proved TNFAIP3 as deubiquitinating enzyme to increase TRAF1 stability, further inducing pyroptosis.

The VacA/TNFAIP3/TRAF1 signaling cascade facilitates pyroptosis in H. pylori- infected tissue. Overactivation of Pyroptosis caused the atrophy-like morphological changes of gastric epithelium, further inducing sustainable malignant transformation.

Kidney stones represent a highly prevalent urological disorder worldwide, with high incidence and recurrence rates. Calcium oxalate (CaOx) crystal-induced kidney injury serves as the foundational mechanism for the formation and progression of CaOx stones. Regulated cell death (RCD) such as ferroptosis, necroptosis, and pyroptosis are essential in the pathophysiological process of kidney injury. Ferroptosis, a newly discovered RCD, is characterized by its reliance on iron-mediated lipid peroxidation. Necroptosis, a widely studied programmed necrosis, initiates with a necrotic phenotype that resembles apoptosis in appearance. Pyroptosis, a type of RCD that involves the gasdermin protein, is accompanied by inflammation and immune response. In recent years, increasing amounts of evidence has demonstrated that ferroptosis, necroptosis, and pyroptosis are significant pathophysiological processes involved in CaOx crystal-induced kidney injury. Herein, we summed up the roles of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury. Furthermore, we delved into the curative potential of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury.

Ischemia/reperfusion injury (IRI) presents a significant hurdle in lung transplantation. Our previous research showed that the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide (Lir) improves lipopolysaccharide-induced acute lung injury in murine models. This study aims to further investigate the lung-protective mechanisms of GLP-1R agonist.

An in vitro hypoxia/reoxygenation (H/R) model with BEAS-2B cells and an in vivo donation after cardiac death (DCD) rat lung transplant model were utilized. Lir was administered using an ex vivo lung perfusion (EVLP) system. Lung function, injury, and pyroptosis mechanisms were assessed. Validation experiments included quantitative reverse transcription PCR, immunoblot analysis, activity assays and proteomic analysis, among others, to evaluate how GLP-1R agonist protect lungs from IRI by modulating pyroptosis, thereby improving lung function and reducing injury.

Perfusion of the donor lung with Lir using EVLP improved the function of DCD lungs and mitigated IRI. Bioinformatics analysis and validation experiments provided evidence of increased expression of NOD-like receptors signals and pyroptosis in lung transplantation IRI, which was suppressed by Lir treatment. Further investigations revealed that the thioredoxin-binding protein (TXNIP) played a crucial regulatory role in the pyroptosis of IRI, with the NOD-like receptor family pyrin domain-containing 3 (NLRP3) emerging as a key target. In addition, this study found that Lir promotes GLP-1R-dependent TXNIP ubiquitination and modulates TXNIP mRNA stability via the GLP-1R/miR-17 axis.

This study demonstrates, for the first time, that a novel EVLP-based drug delivery approach using GLP-1R agonist can protect lungs from IRI by modulating pyroptosis, thereby improving lung function and reducing injury. The research uncovers a previously unknown mechanism where GLP-1R agonist modulates the protein TXNIP through GLP-1R/miR-17 signaling. These insights underscore the potential of GLP-1R agonists as targeted therapies for primary graft dysfunction in lung transplant recipients, opening new avenues for clinical interventions to improve transplant outcomes.

In the present study, a new type of Caspase-1 homolog is identified from Crassostrea gigas (defined as CgCas1-2D). It is composed of 2×DSRM-CASc domain and has closer evolutionary relationship with mammalian Caspase-1s. The mRNA expressions of CgCas1-2D increase significantly after Vibrio splendidus or LPS stimulation. Recombinant CgCas1-2D and its 2×DSRM and CASc domains all bind various PAMPs and bacteria. rCgCas1-2D shows the highest binding activity to human Caspase-1 substrate. Upon recognizing bacteria, CgCas1-2D co-localizes and interacts with CgGSDME, while it has no cleavage activity to CgGSDME. CgCas1-2D inhibits the histone methylation and acetylation levels and CgNF-κB/Rel nuclear translocation mediated by CgGSDME. In addition, CgCas1-2D suppresses the mRNA expression levels of cytokines mediated by GSDME-NF-κB/Rel axis. The results demonstrate that a new type of anti-inflammatory Caspase-1 identified from oyster upon recognizing various bacteria interacts with GSDME to inhibit the histone modification and NF-κB signaling to suppress the inflammation.

Pyroptosis has attracted significant attention for its role in cancer chemotherapy and immunotherapy. However, few drugs have been reported to induce pyroptosis via the Caspase-3/gasdermin E (GSDME) pathway. Herein, three novel PtIV prodrugs, MRP, DRP, and HRP are rationally designed by conjugating DNA methyltransferase (DNMT) inhibitor (RG108) and/or histone deacetylase (HDAC) inhibitor (PhB) to the PtIV center. These prodrugs can be easily reduced to cisplatin (CDDP) due to the high glutathione (GSH) levels in tumors, liberating the coordinated ligands. Released RG108 reactivates the GSDME gene and reduces pyroptosis in low GSDME-expressing tumor cells. Meanwhile, PhB-induced chromatin loosening enhances CDDP-DNA binding, which not only increases Caspase-3 expression, but also upregulates GSDME. HRP demonstrates superior ability to suppress tumor growth and metastasis while reducing systemic toxicity compared with CDDP. By reactivating GSDME and loosening chromatin, HRP effectively boosts tumor cell pyroptosis and exhibits the most pronounced anticancer performance. These findings highlight HRP's potential as a therapeutic agent for triple-negative breast cancer (TNBC) and offer innovative strategies for combining chemotherapy with immunotherapy. To the best of current knowledge, this is the first report of platinum complexes inducing pyroptosis via the Caspase-3/GSDME pathway in low GSDME-expressing tumor cells.

Yiyi Fuzi powder (YYFZ) is a composite formulation consisting of Fuzi and Coix lacryma-jobi seeds. The synergistic application of these exhibits notable anti-inflammatory properties, playing a crucial role in the management of rheumatoid arthritis (RA). However, the therapeutic advantages and potential mechanism of YYFZ in the treatment of RA are still unclear.

The purpose of this study is to find functional metabolites by metabolomics technology, and to investigate the mechanism of functional metabolites mediating RA inflammation on the basis of collagen-induced arthritis rat fibroblast-like synovial cells (CIA-FLS) model, and to explore the pharmacodynamic material basis of YYFZ.

Utilizing untargeted metabolomics in conjunction with UPLC-Q-TOF/MS and GC-MS, we identified potential functional metabolites of YYFZ. In vitro experiments were conducted to determine pyroptosis-related proteins via Western blot, q-PCR and immunofluorescence, thereby exploring functional metabolic pathways. Subsequently, network pharmacology and molecular docking techniques were employed to evaluate the mode of action and mechanisms of "effective components-key targets", elucidating the active components of YYFZ.

Using untargeted metabolomics, 18 differential metabolites were identified, with palmitic acid (PA) showing high correlation as a potential functional metabolite. MTT experiments revealed that 300 μM PA inhibited CIA-FLS by 50%. Further analysis through in vitro experiments indicated that PA promotes inflammatory factor expression via NLRP3/Caspase-1/GSDMD-N/IL-1β mediated pyroptosis. Network pharmacology and molecular docking of 26 in vitro YYFZ components identified benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypacoitine (BHA) as potential active components. In vitro experiments revealed that these components reduce RA inflammation by targeting pyroptosis.

PA, a functional metabolite, can promote RA inflammatory factors by inducing pyroptosis of NLRP3/Caspase1/GSDMD-N/IL-1β. BAC, BMA and BHA derived from YYFZ have demonstrated efficacy in mitigating the inflammatory damage induced by the functional metabolite PA, suggesting their potential as therapeutic agents for RA. These findings offer valuable insights for the development of targeted therapies for RA and underscore the clinical applicability of YYFZ.

Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder characterised by oxidative stress, neuroinflammation, mitochondrial dysfunction and cerebral insulin resistance. Even though approximately 95 % of AD cases are reported as sporadic, the exact pathogenesis remains sparse. Tranilast, an analogue of tryptophan metabolite, was initially endowed as an anti-allergic agent and used in multiple inflammatory ailments. Still, the molecular mechanisms targeting sAD are yet to be investigated. In the present study, we investigated the neuroprotective potential of tranilast by performing biochemical, molecular and histopathological assessments using both in vivo and in vitro experimental sAD models. Streptozotocin (STZ; 3 mg/kg) was bilaterally injected on day 1 and 3 through the intracerebroventricular (ICV) route to Sprague Dawley rats for the in vivo model induction. Spontaneous alternation test, novel object recognition test, and passive avoidance test were performed to assess the altered behavioural patterns in animals. Furthermore, human neuroblastoma cells (SHSY5Y) were exposed to STZ (1 mM) and tranilast for 24 h to validate the in vivo results. Three weeks of tranilast (30 and 100 mg/kg, p.o.) treatment improved neurobehavioural anomalies in ICV-STZ-treated rats by halting neuroinflammation and NLRP3 inflammasome activation caused by enhanced reactive oxygen species (ROS) and thioredoxin interaction protein (TXNIP) overexpression. The phosphorylated tau (p-tau S416) level was also increased in the ICV-STZ rat's hippocampus and reversed upon tranilast treatment. A high dose of tranilast (100 mg/kg) treatment sensitised hippocampal insulin signalling in ICV-STZ-treated rats. Furthermore, in cell culture studies, 24-h tranilast (30 and 100 μM) treatment reduced the mitochondrial ROS production and attenuated inflammasome activation in STZ-treated SHSY5Y cells. In summary, the findings of the study proclaim the neuroprotective potential of tranilast in STZ induced model of sAD by modulating the TXNIP-NLRP3 inflammasome pathway.

Sepsis-induced lung injury is a serious complication that contributes to the high morbidity and mortality rates in septic patients. This study aims to identify genes associated with sepsis-induced lung injury and evaluate the role of cathepsin B (CTSB) in this process. Here, by analyzing three data sets of sepsis-induced lung injury in mouse models, we identified 23 common differentially expressed genes and performed enrichment analyses. Further experiments demonstrated that CTSB expression was significantly upregulated in the sepsis mouse model, and pre-treatment with the CTSB inhibitor CA-074 markedly improved the survival rate of the mice from 21.05 to 78.95%. In addition, the CTSB inhibitor reduced the systemic inflammatory response in septic mice by decreasing plasma levels of nitric oxide (NO) and the inflammatory cytokines TNF-α and IL-1β.Histological analysis showed that the CTSB inhibitor effectively suppressed CLP-induced lung tissue alterations and neutrophil infiltration, and significantly reduced the expression of inducible nitric oxide synthase (iNOS). Analysis of cell death indicated that the CTSB inhibitor decreased cell death in the lung tissue of CLP mice, particularly by inhibiting the upregulation of gasdermin D-N (GSDMD-N), which is associated with pyroptosis. Furthermore, in vitro experiments revealed that overexpression of CTSB enhanced cell death and promoted pyroptosis in lung epithelial cells. These results indicate that CTSB plays a crucial role in sepsis-induced lung injury, potentially exacerbating the inflammatory response by promoting pyroptosis. Therefore, CTSB may be a potential therapeutic target for sepsis-induced lung injury.

Gasdermin D (GSDMD)-mediated pyroptosis drives inflammatory cytokine release in response to environmental triggers. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, has been demonstrated to inhibit GSDMD pore formation. Although airway epithelial barrier dysfunction contributes to chronic obstructive pulmonary disease (COPD) progression, the role of GSDMD-dependent pyroptosis in ozone-induced pathogenesis, and the potential of DSF to inhibit this process, remain unexplored.

We analyzed the expression levels of pyroptosis-related molecules in airway epithelial cells from COPD patients' samples obtained from the Gene Expression Omnibus (GEO) database and evaluated the potential therapeutic effects of DSF in a mouse model of COPD induced by chronic ozone exposure.

GSDMD was significantly upregulated in the airway epithelial cells of COPD patients. Chronic ozone exposure in mice elevated the cleaved form of GSDMD and reduced the expression of epithelial junctional proteins. DSF treatment effectively inhibited GSDMD-mediated pyroptosis and attenuated epithelial barrier disruption, leading to significant improvements in airway inflammation and lung function in both large and small airways. Furthermore, Gsdmd expression was negatively correlated with the tight junction protein Occludin and pulmonary function indices, including the ratio of FEV25 to FVC and MMEF.

Collectively, these findings revealed the role of GSDMD-mediated pyroptosis in epithelial barrier disruption of COPD and the potential application of DSF in the treatment of COPD.

Hyperuricemia is independently associated with an increased risk of nonalcoholic steatohepatitis (NASH), but the underlying mechanisms responsible for this association remain unclear. We first analyzed the association between intrahepatic UA levels and gasdermin D (GSDMD)-mediated pyroptosis in vivo and in vitro. We subsequently generated hepatic-specific glucose transporter 9 (GLUT9)-knockout mice and GSDMD knockout (GSDMD-/-) mice to explore the role of intrahepatic UA in GSDMD-induced pyroptosis in NASH. We found that high intrahepatic UA levels were positively related to GSDMD-mediated pyroptosis in NASH mice. The inhibition of hepatic UA production by allopurinol alleviated hepatic inflammation and GSDMD-mediated pyroptosis in NASH mice. Hepatic-specific knockout of Glut9 significantly decreased intrahepatic UA levels, attenuated NOD-like receptor family pyrin domain containing 3 (NLRP3)-Caspase-1-GSDMD-mediated pyroptosis in hepatocytes, and ameliorated hepatic inflammation and fibrosis in different mouse models of NASH. Further experiments revealed that inhibiting the NLRP3/Caspase-1/GSDMD pathway obviously blocked UA-induced pyroptosis and inflammation in hepatocytes. Additionally, GSDMD deficiency markedly reversed hepatic inflammation and fibrosis in NASH mice. In conclusion, our results showed that high UA could induce NLRP3-Caspase1-GSDMD-mediated pyroptosis, thereby aggravating NASH in mice.

Inflammatory bowel disease (IBD) is a serious chronic condition marked by persistent and recurrent intestinal ulcers. Although the exact cause of IBD remains unclear, it is generally accepted that a complex interaction among dietary factors, gut microbiota, and immune responses in genetically predisposed individuals contributes to its development. Pyroptosis, an inflammatory form of programmed cell death activated by inflammasomes, is marked by the rupture of cell membranes and the subsequent release of inflammatory mediators. Emerging evidence indicates that pyroptosis plays a crucial role in the pathogenesis of IBD. Moderate pyroptosis activation can enhance intestinal immune defenses, while excessive inflammasome activation can trigger an inflammatory cascade, resulting in increased damage to intestinal tissues. This article reviews the molecular mechanisms underlying pyroptosis and highlights its role in the onset and progression of IBD. Furthermore, We explore recent advancements in IBD treatment, focusing on small molecule compounds that specifically target and inhibit pyroptosis.

Parkinson's disease (PD) is a neurodegenerative disease, and inflammation is a key factor in the progression of PD. S100A9 mediates pyroptosis and implicates in various diseases including PD. Pyroptosis, an emerging form of programmed cell death, usually causes cell rupture and death via an inflammatory response. α-Lipoic acid (α-ALA), a cellular coenzyme, participates in anti-inflammatory and antioxidant processes. Although its role in PD has been confirmed, but the exact mechanism of its anti-inflammatory effect remains unclear. In our research, we examined the potential mechanisms of pyroptosis mediated by S100A9 in PD and the neuroprotective effects of α-ALA. We used 6-hydroxydopamine (6-OHDA) to induce SH-SY5Y cells in vitro and in C57BL/6 mice in vivo. The cell viability of SH-SY5Y cells confirmed the neuroprotective effect of α-ALA. Proteomics analysis indicated that S100A9 was involved in 6-OHDA-mediated neuronal injury, while α-ALA could inhibit. We found that α-ALA ameliorated PD symptoms induced by 6-OHDA and decreased the levels of NLRP3 inflammasome, Gasdermin D, and IL-1β, which are major hallmarks of pyroptosis. Furthermore, our research demonstrated that α-ALA mitigated cell injury by suppressing NLRP3-dependent pyroptosis mediated by S100A9. In brief, pyroptosis is pivotal in PD, while α-ALA protects dopaminergic neurons by suppressing pyroptosis mediated through the NLRP3 inflammasome, directly reducing S100A9, and subsequently inhibiting the NLRP3/Gasdermin D signaling pathways. Our results collectively suggest that suppressing S100A9-mediated pyroptosis and administering α-ALA may represent a novel approach in treating of PD.

Photodynamic therapy (PDT) can induce tumor cell death. Ru3, a metal-based photosensitizer, features a high positive charge, a long triplet excited-state lifetime, and an excellent PDT activity. The aptamer AS1411, known for its ability to selectively bind to nucleolin (which is overexpressed in tumor cells), self-assembled with Ru3 into nanoparticles termed Ru3ApNPs. These nanoparticles specifically target SiHa tumor cells. Upon light irradiation, Ru3ApNPs increase intracellular ROS levels, catalyze NADH redox reactions, and induce lysosomal disruption, ultimately triggering pyroptosis in tumor cells. Notably, Ru3ApNPs demonstrate excellent tumor penetration in 3D multicellular spheroids (MCSs) of SiHa cells and effectively inhibit their growth under light exposure. Ru3ApNPs exhibit a mechanism of action distinct from that of traditional PDT. Furthermore, under light irradiation, Ru3ApNPs can effectively inhibit the growth of distant tumors and induce systemic immune responses in mice. Our data suggest that Ru3ApNPs can be developed as promising targeted therapeutic agents in the future.

Qilian Jiechang Ning (QJN), a traditional Chinese herbal formula, has demonstrated potential therapeutic effects in the treatment of ulcerative colitis (UC). This study aims to investigate the mechanism of QJN in the outer membrane vesicles (OMVs) of Segatella copri (S. copri)-induced colon epithelial cells and UC mice.

Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were utilized to assess the morphology and size of OMVs. Inflammation markers and tight junction protein levels in HCoEpiCs induced by OMVs were monitored using ELISA and western blot. QJN was administered to intervene in HCoEpiCs treated with S. copri OMVs. Additionally, trinitrobenzene sulfonic acid (TNBS)-induced mouse models were conducted to evaluate the therapeutic effects of QJN on UC.

S. copri OMVs treated with QJN demonstrated a significant reduction in particle size, protein concentration, and LPS content. In HCoEpiCs, QJN effectively decreased the expression of inflammation-inducing cytokines (IL-1β, IL-18, IL-6, TNF-α) and proinflammatory proteins (GSDMD-N, NLRP3, ASC, cleaved Caspase-1, cleaved Caspase-4) triggered by S. copri OMVs, while enhancing the expression of tight junction proteins (ZO-1 and Occludin). In the UC mouse models, QJN significantly reduced the Disease Activity Index (DAI), improved colon length, lowered LPS levels, ameliorated colonic tissue damage, and inhibited Caspase-1- and Caspase-11-dependent inflammatory responses.

QJN can alleviate S. copri-OMV-induced inflammatory response in colonic epithelial cells and reduce symptoms of UC in mouse models by modulating the Caspase-1 and Caspase-11 pathways.

Intracerebral hemorrhage (ICH) is often linked to severe neurological impairments, including cognitive deficits and anxiety-like behaviors. This study aimed to evaluate the therapeutic potential of PTEN-induced kinase 1 (PINK1), which is activated during ICH, as a target for mitigating these effects. C57/BL6 wild-type mice underwent ICH induction through an intrastriatal injection of autologous blood. The PINK1 activator, MTK458, was administered daily doses of 10-50 mg/kg starting one week before ICH induction and continuing for three days post-surgery. The modified neurological severity score (mNSS) was used to assess neurological deficits, while brain edema was measured through brain water content. The open field test and Y-maze test were used to evaluate anxiety-like behavior, and cognitive function respectively. The effects of ICH on cortical cell pyroptosis, Parkin/PINK1-mediated mitophagy, and the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome were analyzed via Western blotting, ELISA, and qRT-PCR. MTK458 effectively reduced brain water content in the basal ganglia, ipsilateral cortex, and cerebellum, with improvements in mNSS extending to 14 days post-injury. Additionally, MTK458 alleviated both neurological deficits and anxiety-like behavior in ICH mouse models. It also reversed ICH-induced cortical cell pyroptosis by promoting Parkin/PINK1-mediated mitophagy and inhibiting NLRP3 inflammasome activation, as well as the expression of IL-1β and IL-18. These results suggest that MTK458 effectively reduces neurological impairments, brain edema, and anxiety-related behaviors in mice following ICH, highlighting PINK1 activation as a promising therapeutic strategy for ICH-induced neurological deficits.

Great advances have been made in malignant melanoma treatments, whereas drug resistance still limits many drug applications. CRKL has been reported to be overexpressed in various tumors and showed poor prognosis. However, its specific function and mechanism in melanoma remain unclear. In the present study, we investigated the expression of CRKL and its clinical association by bioinformatics and clinical analysis, and then performed a series of in vitro and in vivo experiments to demonstrate its function and mechanism. Results showed that CRKL increased during melanoma progression and was strongly associated with poor prognosis. CRKL silencing effectively inhibited melanoma cell growth and invasion via ERK/MMP9 and PI3K/AKT signaling pathways both in vitro and in vivo. Moreover, CRKL silencing induced pyroptosis in melanoma cells by upregulating the levels of pyroptosis-associated proteins, such as NLRP3, cleaved Caspase-1, and GSDMD-N. Importantly, our study demonstrated that interfering with CRKL expression enhanced the chemotherapy sensitivity of melanoma cells to cisplatin by regulating PI3K/AKT and NLRP3/GSDMD signaling pathways. In conclusion, our study uncovers a novel molecular mechanism by which CRKL functions in melanoma and highlights potential therapeutic strategies for improving chemotherapy sensitivity in melanoma patients.

A series of cyclometalated Ir(III)-lonidamine (LND) complexes (Ir-LND-1-6) with the formula [Ir(C^N)2bpy(4-CH3-4'-CH2OLND)](PF6) (Ir-LND-1-3) and [Ir(C^N)2bpy(4-CH2OLND-4'-CH2OLND)](PF6) (Ir-LND-4-6) (C^N = 2-phenylpyridine (ppy, in Ir-LND-1 and Ir-LND-4), 2-(2-thienyl) pyridine (thpy, in Ir-LND-2 and Ir-LND-5) and 2-(2,4-difluorophenyl) pyridine (dfppy, in Ir-LND-3 and Ir-LND-6)), were designed and synthesized. 3-(4,5-dimethylthiazol-2-yl)-2,5-biphenyltetrazolium bromide (MTT) assay data showed that the cytotoxicity of Ir-LND-1-3 carry one LND moiety was superior to that of Ir-LND-4-6 with two LND moieties. Therefore, we selected Ir-LND-1-3 as model compounds to investigate the anti-tumor mechanism of the Ir(III)-LND system. The results showed that Ir-LND-1-3 could inhibit cancer cell migration and colony formation. In addition, Ir-LND-1-3 could penetrate into HeLa cells and localized to mitochondria, further disrupting mitochondrial membrane potential (MMP), increasing intracellular reactive oxygen species (ROS), and reducing intracellular adenosine triphosphate (ATP). Further exploration of anti-tumor mechanisms showed that pyroptosis was the main mode of Ir-LND-1-3 induced cell death, manifested as membrane perforation and swelling, activation of caspase-3 and cleavage of Gasdermin E (GSDME), as well as release of lactic dehydrogenase (LDH) and ATP. The pyroptosis induced by Ir-LND-1-3 also initiated immunogenic cell death (ICD) by triggering the release of calreticulin (CRT) and high mobility group protein b1 (HMGB1) on the cell surface.

Liver X receptors (LXRs) play a key role in cholesterol transport, glucose metabolism and the tumorigenesis. LXR ligands can inhibit tumor growth through several mechanisms, such as suppressing tumor cell proliferation and migration, and inducing tumor cell death. Among them, induction of tumor cell death is one of the main mechanisms by which LXR ligands inhibit tumor growth; but how exactly LXR ligands cause cell death is still unclear. In this study, we found that LXR agonists can induce nonclassical pyroptosis in various cancer cells. Further study we found that Caspase-3-mediated GSDME cleavage is involved in LXR agonist-induced pyroptosis. Mechanically, LXR agonists firstly induce ER stress in tumor cells, then the ER stress induced by LXR agonists alters the integrity of the mitochondrial outer membrane (MOM) through the NOXA and BAX/BAK. Subsequently, mitochondrial permeability transition activates Caspase-4/APAF-1 pyroptosome to activate GSDME-dependent pyroptosis. Finally, we also found that LXR agonists induced GSDME-dependent pyroptosis in mouse cells. Our results demonstrated that LXR agonists can induce nonclassical GSDME-dependent pyroptosis in cancer cells by inducing ER stress, which alters the integrity of MOM to activate Caspase-4/APAF-1 pyroptosome.

Plasma membrane rupture (PMR), the ultimate event during lytic cell death, releases damage-associated molecular patterns (DAMPs) that trigger inflammation and immune responses in the development of various diseases. Recent years have witnessed significant advances in understanding the PMR mediated by ninjurin1 (NINJ1) in different lytic cell death processes. NINJ1 oligomerizes and ruptures the membrane in pyroptosis and other lytic cell death, participating in the pathogenesis of multiple diseases. Although the membrane-permeabilizing function of NINJ1 is well recognized, the role of NINJ1 in different types of lytic cell death and its impact on multiple disease processes have yet to be fully elucidated. This review summarizes the latest advances in the mechanisms of NINJ1-mediated PMR, discusses the membrane-inducing activity of NINJ1 in different lytic cell death, explains the implications of NINJ1 in lytic cell death-related diseases, and lists the inhibitory strategies for NINJ1. We expect to provide new insights into targeting NINJ1 to suppress lytic cell death for therapeutic benefit, which may become a new strategy to control inflammatory cell lysis-related diseases.

Pyroptosis is an inflammatory form of programmed cell death with great potential in cancer immunotherapies. Photodynamic therapy (PDT) represents a promising treatment modality to trigger pyroptosis. However, the hypoxic microenvironment inside the tumors often induces limited therapeutic efficacy. Herein, in this work, the first type of mitochondrial-targeting oxime-ester photogenerator (T-Oximer) was constructed to boost type-I ROS/aryl free radicals which could induce DNA damage by DNA cleaving and facilitate high-efficiency pyroptosis-mediated photoimmunotherapy. Detailed mechanism investigations revealed that T-Oximer could produce aryl free radicals via photolysis reaction and generate type-I ROS (O2 •- and •OH) based on the type-I electron transfer process. Meanwhile, T-Oximer could accumulate in the mitochondria, boost mitochondrial radicals, and damage mitochondria in hypoxic tumor cells. Of peculiar interest, T-Oixmer could bind with DNA and cleave DNA to induce DNA damage. Combined mitochondrial damage with DNA cleavage, T-Oximer can initiate pyroptosis, activate the ICD effect, and trigger robust systemic antitumor immunity for efficient tumor regression and metastasis suppression. Our finding provides a new strategy for constructing oxygen-independent photogenerator for high-efficiency pyroptosis-mediated anti-hypoxia photoimmunotherapy.

Ca2+ overload is one of the most widely causes of inducing apoptosis, pyroptosis, immunogenic cell death, autophagy, paraptosis, necroptosis, and calcification of tumor cells, and has become the most valuable therapeutic strategy in the field of cancer treatment. Nevertheless, several challenges remain in translating Ca2+ overload-mediated therapeutic strategies into clinical applications, such as the precise control of Ca2+ dynamics, specificity of Ca2+ homeostasis dysregulation, as well as comprehensive mechanisms of Ca2+ regulation. Given this, we comprehensively reviewed the Ca2+-driven intracellular signaling pathways and the application of Ca2+-based biomaterials (such as CaCO3-, CaP-, CaO2-, CaSi-, CaF2-, and CaH2-) in mediating cancer diagnosis, treatment, and immunotherapy. Meanwhile, the latest researches on Ca2+ overload-mediated therapeutic strategies, as well as those combined with multiple-model therapies in mediating cancer immunotherapy are further highlighted. More importantly, the critical challenges and the future prospects of the Ca2+ overload-mediated therapeutic strategies are also discussed. By consolidating recent findings and identifying future research directions, this review aimed to advance the field of oncology therapy and contribute to the development of more effective and targeted treatment modalities.

Pyroptosis has been reported to play a pathogenic role in neonatal hypoxic-ischemic brain damage (HIBD). Absence in melanoma 2 (AIM2) is an inflammasome involved in pyroptosis.

This study aimed to investigate the role of AIM2 in hypoxic-ischemia (HI)-induced pyroptosis and brain damage in a neonatal rat HIBD model.

In vivo, we injected a lentivirus that overexpressed or knocked down AIM2 into the lateral ventricle of rats within 24 h after birth and prepared a 7-day Sprague Dawley (SD) rat HIBD model. In vitro, we transfected lentiviruses overexpressing or knocking down AIM2 into cultured primary neurons and established an oxygen/glucose deprivation/reoxygenation (OGD/R) model. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to determine infarct size. Hematoxylin and eosin and Nissl staining were used to evaluate morphological changes in the damaged brain. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays were used to determine cell viability and toxicity. Pyroptosis was observed using transmission electron microscopy.

AIM2 expression significantly increased in the HI-induced cortex of neonatal rats. Lentivirus-mediated overexpression of AIM2 significantly aggravates HI-induced brain injury and OGD/R-induced neuronal injury in vivo and in vitro. The lentivirus-mediated AIM2 knockdown significantly reversed these adverse effects. In addition, AIM2 overexpression increased HI-induced pyroptosis in neonatal rats in vivo and in vitro, whereas AIM2 knockdown suppressed HI-induced pyroptosis via the AIM2/Caspase-1/GSDMD pathway.

These findings show that the upregulation of AIM2 activates pyroptosis and plays a pathogenic role in neonatal HIBD.

Bladder cancer therapy remains challenging due to poor efficacy and frequent recurrence. Mannose, a naturally occurring monosaccharide, has demonstrated antitumor effects in various cancers, yet its mechanism of action in bladder cancer is unclear. This study explored the inhibitory effects of mannose on bladder cancer. We found mannose significantly inhibited the growth of bladder cancer cells, xenografts, and organoids. Mannose directly binds to PKM2, inhibiting its enzymatic activity and reducing lactate production. This reduction in lactate led to decreased PKM2 lactylation and increased acetylation, causing PKM2 to translocate to the nucleus. Nuclear PKM2 activated the NF-κB pathway, inducing NLRP1/Caspase-1/GSDMD/IL-1β-dependent pyroptosis. Additionally, mannose promoted antitumor immune responses by inducing pyroptosis and enhancing the efficacy of immune checkpoint inhibitors. These findings highlight the use of mannose as a potent antitumor agent and a promising therapeutic strategy for bladder cancer.

Neonatal hypoxic-ischemic brain damage is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), a derivative of N-acetylserotonin, has shown neuroprotective properties. This study was conducted to evaluate the neuroprotective and molecular mechanisms of HIOC. We established an in vitro model using Oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells, alongside an in vivo model via the modified Rice-Vannucci method. The results showed that HIOC reduced OGD/R-induced HT22 cell pyroptosis and inhibited NOD-like receptor pyrin domain- containing protein 3 (NLRP3) inflammasome activation. With the addition of the mitophagy inhibitor 3-MA, we demonstrated that HIOC promoted PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy to reduce HT22 cell pyroptosis. Mechanistically, HIOC stimulated mitophagy to remove damaged mitochondria. The clearance of injured mitochondria reduced reactive oxygen species generation, which consequently inhibited NLRP3 inflammasome expression. In vivo, HIOC remarkably lessened cerebral blood flow, infarct volume, neuronal injury by activating mitophagy. HIOC activated mitophagy to produce antipyroptosis effects. Together, our finding demonstrated that HIOC improves brain injury by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis, suggesting its potential for hypoxic-ischemic brain damage treatment.

Sepsis-associated acute kidney injury (S-AKI) is a severe complication characterized by high morbidity and mortality, driven by multi-organ dysfunction. Recent evidence suggests that pyroptosis, a form of programmed cell death distinct from apoptosis and necrosis, plays a critical role in the pathophysiology of S-AKI. This review examines the mechanisms of pyroptosis, focusing on inflammasome activation (e.g., NLRP3), caspase-mediated processes, and the role of Gasdermin D in renal tubular damage. We also discuss the contributions of inflammatory mediators, oxidative stress, and potential therapeutic strategies targeting pyroptosis, including inflammasome inhibitors, caspase inhibitors, and anti-inflammatory therapies. Lastly, we highlight the clinical implications and challenges in translating these findings into effective treatments, underscoring the need for personalized medicine approaches in managing S-AKI.

Copper is a trace element which is essential for biological organisms, and its homeostatic balance is important for living organisms to maintain the normal function. When the copper homeostasis is disordered, the cellular function and structure will be disrupted. Excess copper cause oxidative stress and DNA damage in cells, thereby inducing regulated cell death such as apoptosis and necroptosis. Excess copper in mitochondria can bind to lipoylated proteins in the tricarboxylic acid (TCA) cycle and cause them to aggregate, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cancer cells have a greater demand for copper compared to normal tissue, and high levels of copper ions are closely associated with tumour proliferation and metastasis. The anti-tumor mechanisms of copper include the production of oxidative stress, inhibition of the ubiquitin-proteasome system, suppression of angiogenesis, and induction of copper-dependent cell death. Targeting copper is one of the current directions in oncology research, including the use of copper ion carriers to increase intracellular copper levels to induce oxidative stress and cuproptosis, as well as the use of copper ion chelators to reduce copper bioavailability. However, copper complexes have certain toxicity, so their biosafety needs to be improved. Emerging nanotechnology is expected to solve this problem by utilizing copper-based nanomaterials (Cu-based NMs) to deliver copper ions and a variety of drugs with different functions, thereby improving the anti-tumor efficacy and reducing the side effects. Therefore, a thorough understanding of copper metabolic processes and the mechanism of cuproptosis will greatly benefit anti-tumor therapy. This review summarizes the processes of copper metabolism and the mechanism of cuproptosis. In addition, we discuss the current anti-tumor paradigms related to copper, we also discuss current nanotherapeutic approaches to copper mortality and provide prospective insights into the future copper-mediated cancer therapy.

As a form of inflammation-associated cell death, pyroptosis has gained widespread attention in recent years. Accumulating evidence indicates that pyroptosis regulates tumor growth and is associated with autoimmune disorders and inflammatory response. Paclitaxel, a traditional Chinese medicine, usually induces death of cancer cells as a chemotherapeutic agent. Previous studies have revealed that paclitaxel can exert an anti-tumor effect through a variety of cell death mechanisms, of which pyroptosis plays a pivotal role in inhibiting tumor growth and enhancing anti-tumor immunity. In this review, we summarize the current advances in therapeutic connections between pyroptosis and paclitaxel in anti-tumor effects.

Caerin peptides exhibit a dual role in cancer treatment by directly killing cancer cells and modulating the tumour microenvironment to enhance anti-tumour immunity. This study investigates the mechanisms underlying caerin 1.1/1.9-induced acute cell death in epithelial cancer cells and explores their therapeutic potential. HeLa, A549, and Huh-7 cancer cell lines were treated with caerin 1.1/1.9 peptides. Morphological observations, flow cytometry, lactate dehydrogenase (LDH) release, and IL-18 secretion assays revealed the occurrence of pyroptosis following treatment. Specifically, a 1-h treatment with caerin 1.1/1.9 induced pyroptosis in HeLa, A549, and Huh-7 cells, characterised by cell swelling, membrane bubbling, and the release of IL-18 and LDH. Western blotting confirmed the upregulation of pyroptosis markers, including caspase-3, cleaved caspase-3, and GSDME-N fragments. These findings highlight the significant role of caerin peptides in inducing acute pyroptosis, a form of programmed cell death that enhances the immunogenicity of dying cancer cells, thus potentially improving the effectiveness of immunotherapies. This research underscores the therapeutic potential of caerin 1.1/1.9 peptides in cancer treatment, providing a foundation for developing new anti-cancer strategies that leverage both direct cytotoxic effects and immune modulation to achieve more effective and sustained anti-tumour responses.

Human immunodeficiency virus (HIV) infection in humans can cause a variety of symptoms. Among these, acquired immunodeficiency syndrome (AIDS) remains the most severe form. Current treatment of HIV/AIDS with antiretroviral drugs effectively inhibits HIV replication and infection and significantly extends the lifespan of HIV/AIDS patients. However, antiretroviral drugs cannot completely remove HIV from patients due to the high latency of HIV, and they possess side effects and can lead to drug resistance. HIV/AIDS remains to be an incurable disease, and new methods and drugs are still desirable. Inflammasomes were found to be activated during HIV infection and regulate AIDS progression. Previous reviews provide a simple summary of inflammasome activators and inhibitors during HIV infection without distinguishing the specific infection stage, this kind of summary does not provide any clinical target value. Here, we provide a comprehensive review of inflammasomes in HIV/AIDS according to the infection timeline and propose several inflammasome target strategies for clinical HIV/AIDS treatment. We systematacially summarized the activation and function of kinds inflammasomes during the different HIV infection stages, with the aim of providing new therapeutic targets and directions for HIV/AIDS and HIV-associated comorbidities.

Intervertebral disc degeneration (IVDD), a prevalent degenerative disorder with substantial socioeconomic impacts, is closely linked to endplate inflammation and chronic low back pain. Its pathogenesis involves multifactorial mechanisms, including long-term chronic mechanical loading, external trauma, and hereditary factors. Emerging evidence highlights Propionibacterium acnes (P. acnes), a gram-positive bacterium with potent proinflammatory properties, as a key contributor to IVDD progression. This review systematically analyses the latest literature on related studies, focusing on the molecular mechanisms of IVDD induced by P. acnes. Three molecules play an important role in the induction of IVDD by P. acnes, namely, IL-1β, MIF, and MMP. In addition, P. acnes induces IVDD through three core mechanisms, namely, proinflammatory (activation of TLR2, production of large amounts of ROS to promote inflammation), pyroptosis (production of large amounts of NLRP3 through the TXNIP-NLRP3 axis and the ROS-NLRP3 axis), and apoptosis (promotion of Bax and inhibition of Bcl-2 expression through the TLR2-JNK pathway). The dissection of these related important molecules and pathogenic mechanisms can lead to a better understanding of the role of P. acnes in IVDD. It can provide an important theoretical basis for future research. However, the current study's lack of large-scale clinical validation, unresolved colonization controversies, and limited experimental methods are limitations. Therefore, in the future, it is still necessary to improve the relevant theories and resolve the current controversies through more advanced experimental methods and higher quality clinical studies. In conclusion, the study of P. acnes-induced IVDD is promising, and further research can be conducted in the future, which is expected to develop novel therapeutic approaches for P. acnes, thus effectively slowing down the development of IVDD.

Acute myocardial infarction (AMI) and the myocardial ischemia-reperfusion injury (MI/RI) that typically ensues represent a significant global health burden, accounting for a considerable number of deaths and disabilities. In the context of AMI, percutaneous coronary intervention (PCI) is the preferred treatment option for reducing acute ischemic damage to the heart. Despite the modernity of PCI therapy, pathological damage to cardiomyocytes due to MI/RI remains an important target for intervention that affects the long-term prognosis of patients. In recent years, mitochondrial dysfunction during AMI has been increasingly recognized as a critical factor in cardiomyocyte death. Damaged mitochondria play an active role in the formation of an inflammatory environment by triggering key signaling pathways, including those mediated by cyclic GMP-AMP synthase, NOD-like receptors and Toll-like receptors. This review emphasizes the dual role of mitochondria as both contributors to and regulators of inflammation. The aim is to explore the complex mechanisms of mitochondrial dysfunction in AMI and its profound impact on immune dysregulation. Specific interventions including mitochondrial-targeted antioxidants, membrane-stabilizing peptides, and mitochondrial transplantation therapies have demonstrated efficacy in preclinical AMI models.

The homeostasis of gastric mucosa is extremely delicate. Neutrophils, the most abundant immune cells in human circulation, are regarded crutial in the regulation of gastric mucosal immune response. Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury is the second major reason for gastric ulcers. The relations between neutrophils and Indomethacin-induced gastric injury are not fully understood. A mouse model of gastric injury was established using Indomethacin, followed by proteomic analysis (raw data are available via ProteomeXchange with identifier PXD058482). GO functional annotations and KEGG pathway enrichment analysis were conducted on significant differential proteins. The formation of neutrophil extracellular traps (NETs) was observed using ELISA and immunofluorescence. TEM, Western blot and Real-time PCR were applied to observe programmed death of gastric epithelial cells (GECs), and ELISA was conducted to measure levels of TNF-α and IL-1β in the gastric tissue. Deoxyribonuclease 1 (DNase 1), a NETs inhibitor, was administered intraperitoneally to inhibit NETs formation. In vitro, neutrophils were isolated from peripheral blood of mice and co-cultured with mouse GECs cell line, different dosage of Indomethacin were added to the culture dish, the levels of inflammatory factors, formation of NETs and GECs programmed death were assessed in vitro. Poly morphonuclear neutrophils (PMN) were extracted from mouse peripheral blood and single-cell RNA-sequencing (scRNA-seq) was further applied (raw data are available via Genome Sequence Archive with identifier CRA020950) to explore the intracellular mechanism of NETs formation. ELISA and immunofluorescence were performed to validate expression of IL-17 signaling pathway. After Indomethacin gavage, obvious gastric injury was observed. Proteomic analysis indicated that NETs formation played a crucial role in Indomethacin-induced gastric injury. Compared to control group, Indomethacin treatment resulted in NETs formation, elevated levels of TNF-α and IL-1β and GECs programmed death. Inhibition of NETs significantly reduced inflammatory factor levels and mitigated gastric injury caused by indomethacin. In vitro, 200 µL, 400 µL and 600 µL of Indomethacin caused excessive NETs formation in neutrophils. Besides, Indomethacin-induced NETs formation led to GECs programmed death in vitro. scRNA-seq revealed that neutrophils enrichment in the peripheral blood of Indomethacin-induced gastric injury and IL-17 signaling might be the key intracellular of NETs formation. Expressions of neutrophil IL-17R and concentration of IL-17 were significantly higher in model group. NETs formation is pivotal in Indomethacin-induced gastric injury, contributing to programmed cell death of GECs and inflammation; IL-17 signaling might be the key intracellular mechanism of NETs formation.

Acute lung injury (ALI), which can progress to acute respiratory distress syndrome (ARDS), has inflammation as a crucial factor, especially the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome involvement. Stromal interaction molecule 1 (STIM1) can block NLRP3 activation, but the mechanism is unclear. Vanillic acid, possessing anti-inflammatory properties, has a role in acute lung injury (ALI) whose specific mechanism remains unclear. This study aimed to investigate the effectiveness of vanillic acid in ALI induced by lipopolysaccharides (LPS) and to elucidate the potential mechanisms. In vitro and in vivo experiments were conducted using cells and a mouse model to find out the impact and underlying mechanisms. We found that vanillic acid demonstrated significant inhibition of IL-1β and IL-18 release triggered by LPS and nigericin in J774A.1 cells. The in vivo findings indicated that vanillic acid not only mitigated acute lung injury but also suppressed NLRP3 inflammasome activation in mice. Mechanistically, vanillic acid inhibited the LPS-induced increase in STIM1 expression through the lysosomal degradation pathway. The reduced STIM1 expression diminished intracellular Ca2+ levels, thereby suppressing inflammasome activation and impeding the cleavage and maturation of Caspase-1 and GSDMD, and eventually attenuating cell pyroptosis. Vanillic acid exerts its inhibitory effects on NLRP3 inflammasome activation by promoting STIM1 degradation, thereby ameliorates ALI through impeding NLRP3-GSDMD mediated pyroptosis. The STIM1-NLRP3 signaling axis represents a promising avenue for potential therapeutic interventions in ALI.

The transcription factor FoxO3a plays a crucial role in the process of cells adapting to various stress conditions. Multiple post - translational modifications and epigenetic mechanisms work together to precisely regulate the activity of FoxO3a, influencing its subcellular localization, stability, interactions with other proteins, DNA - binding affinity, and transcriptional regulatory capacity. Under different chemical signal stimuli and subcellular environments, the activation of FoxO3a triggered by oxidative stress can initiate diverse transcriptional programs, which are essential for the body to resist oxidative damage. In the development and progression of inflammatory diseases, FoxO3a exerts an important function by regulating the expression levels of antioxidant enzymes and participating in key physiological processes such as programmed cell death. This article comprehensively reviews the structural characteristics, mechanism of action of FoxO3a, as well as its functions in regulating antioxidant enzymes and programmed cell death. The aim is to deeply explore the potential of FoxO3a as a potential therapeutic target for preventing and treating damages such as inflammatory diseases caused by cellular stress.

The aim of this study was to determine whether oxidative stress-induced premature senescence in mouse auditory cell line HEI-OC1 cells in vitro is associated with NLRP3 inflammasome activation and pyroptosis, and whether melatonin has a protective effect. HEI-OC1 cells were exposed to different concentrations of hydrogen peroxide (H2O2) to induce oxidative stress and subsequently analyzed by Western blotting to measure pyroptosis-related proteins - NLRP3, caspase-1, and GSDMD-N. Compared with untreated control cells, exposure to different concentrations of hydrogen peroxide (H2O2) promoted premature senescence of HEI-OC1 cells, accompanied by a significant increase in levels of pyroptosis-related proteins - NLRP3, caspase-1, and GSDMD-N. Furthermore, melatonin treatment was shown to decrease the expression of these proteins in HEI-OC1 cells and attenuate the H2O2-induced senescence process. NLRP3 inflammasome activation contributes to oxidative stress-induced premature senescence of HEI-OC1 cells in vitro, leading to pyroptosis. Melatonin attenuates pyroptosis and senescence in HEI-OC1 cells by inhibiting the expression of NLRP3, caspase-1, and GSDMD-N, providing reliable evidence for melatonin as a potential therapeutic agent for age-related hearing loss.

Psoriasis is a common immune-related polygenic inflammatory skin disease. Salidroside (SAL) exerts anti-inflammatory and antioxidant effects and is used to treat skin diseases. However, the specific effects of SAL on psoriasis remain unclear. In this study, we aimed to investigate the efficacy of SAL for psoriasis treatment. Mice were treated with imiquimod (IMQ) to establish an in vivo psoriasis model. Histological analysis was conducted via hematoxylin and eosin staining. Cytokine release was determined via enzyme-linked immunosorbent assay. Additionally, mRNA levels were determined via reverse transcription-quantitative polymerase chain reaction. Protein expression was assessed via Western blotting. Gasdermin D (GSDMD) and Ki-67 expression levels were determined via immunohistochemistry. Caspase 1 and GSDMD expression levels were determined via immunofluorescence assay. Furthermore, macrophage function and keratinocyte pyroptosis were also analyzed via flow cytometry. Cell proliferation was determined using 5-ethynyl-2'deoxyuridine assay. SAL alleviated IMQ-induced psoriasis. IMQ-mediated GSDMD-driven pyroptosis and keratinocyte hyperproliferation promoted M1 macrophage polarization. However, SAL treatment suppressed GSDMD expression, thereby inhibiting keratinocyte proliferation and pyroptosis and promoting M2 macrophage polarization. GSDMD deficiency further promoted the effects of SAL and suppressed psoriasis progression. Overall, our findings suggest that SAL exerts protective effects against psoriasis. Specifically, it exerts anti-inflammatory effects by regulating M2 macrophage polarization and inhibiting keratinocyte pyroptosis-driven proliferation induced by the immune microenvironment in psoriasis.