Apoptosis最新文献

Despite the crucial role of antigen presentation in immune checkpoint inhibitor (ICI) efficacy, its contribution and the mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear, representing a key knowledge gap in overcoming immune escape in its immunotherapy. This study explores how tumor antigen presentation and intercellular interactions in the tumor microenvironment (TME) drive ICI resistance using single-cell RNA sequencing (scRNA-seq). Publicly available scRNA-seq data from 24 ESCC patients treated with chemotherapy and ICIs were analyzed. Cell clustering, transcription factor regulation, cell–cell communication analysis, and KEGG/GO enrichment analyses were used to examine malignant cell heterogeneity, the relationship between antigen-presenting cells and ICI responses, and cell–cell interactions influencing anti-tumor response. Spatial relationships were validated through multiplex immunofluorescence. Malignant cells were classified by enrichment analyses into cNMF_1, cNMF_2, cNMF_3, and cNMF_4, with cNMF_4 showing antigen-presenting traits. Based on ICI response groups, cell–cell communication analysis revealed that in poor responders, the antigen presentation ability of tumors induced by treatment was enhanced, and mainly enriched in the MHC-I pathway. The crosstalk between Progenitor CD8⁺ Tex and hyper-Treg in the TME drove ICI resistance. Hyper-Treg likely regulated CD8⁺ T activation through the CLEC2C-KLRB1 axis, forming an inhibitory cell interaction network dominated by hyper-Treg, resulting in an overall strong immune suppression state of the TME in this population. The antigen-presenting malignant epithelial cells of ESCC exhibit significant interactions with various T cells in the TME. ICI resistance is closely associated with the crosstalk between progenitor CD8⁺ Tex and hyper-Treg, representing a promising target for personalized ESCC therapy.

Cervical cancer (CC) remains a significant global health challenge. A deeper understanding of the molecular mechanisms driving CC progression is crucial for developing improved therapeutic strategies. CSN5 is vital in cell functions and cancer, but its role in CC is unclear. This study aims to explore CSN5’s role and its target gene in CC progression, assessing their potential as therapeutic targets. We employed an integrated approach combining bioinformatics analysis, proteomic profiling, and in vitro and in vivo functional assays. Immunohistochemistry was used to analyze CSN5 and ENO3 expression in CC and normal tissues. CSN5 upregulation was associated with advanced clinical stage and poor differentiation. Furthermore, CSN5 overexpression enhanced cellular proliferation and glycolytic metabolism but, paradoxically, suppressed migration, invasion, and the epithelial-mesenchymal transition (EMT). These pro-tumorigenic effects were confirmed in vivo, and the glycolytic inhibitor 2-DG was found to reverse the phenotypes induced by CSN5. Protein sequencing highlighted ENO3’s role in CSN5-mediated tumorigenesis, regulating EMT and glycolysis by stabilizing its ubiquitination degradation through CSN5. Crucially, silencing ENO3 attenuated the oncogenic effects of CSN5 both in vitro and in vivo. Our findings unveil a novel mechanistic paradigm in which CSN5 promotes CC progression by co-opting ENO3 to enhance glycolytic flux while concurrently suppressing cell motility. This study not only deepens the understanding of CC pathogenesis but also identifies the CSN5-ENO3 axis as a promising target for novel therapeutic interventions.

Graphical abstract

Inflammation, especially invasive bacterial inflammation, has always been a hot topic in medical research. With the emergence of superbugs and highly virulent viruses, current treatment methods are gradually revealing areas of deficiency. As an inflammatory form of cell death, the concept of pyroptosis offers new possibilities for the treatment of inflammation. Pyroptosis is typically triggered by inflammasomes and executed by the Gasdermin (GSDM) family. It is characterized by membrane perforation, cell swelling, and the release of cellular contents such as pro-inflammatory factors. Pyroptosis plays a crucial role in host immune defense, inflammatory diseases, and tumor regulation. In this review, we comprehensively explored each member of the GSDM family and its activation pathways, reviewed the cellular consequences of GSDM activation, and the role of GSDM-mediated pyroptosis in inflammatory diseases such as sepsis. We also provided a detailed account of the latest advancements in inflammation control targeting GSDM, aiming to offer new perspectives for precise therapies targeting pyroptosis.

Graphical abstract

During anesthesia, significant hemodynamic changes often alter the vascular microenvironment and affecting endothelial cell behavior. Propofol, a commonly used intravenous anesthetic, has been widely studied for its role in tumor angiogenesis through tumor cell–derived VEGF–mediated endothelial interactions. However, its direct effects on endothelial cell–mediated angiogenesis in non-malignant diseases such as diabetic retinopathy, diabetic nephropathy, and coronary heart disease remain unclear. To address this gap, we examined the effects of propofol on VEGFA-mediated angiogenesis in vitro and in vivo. Mechanistically, propofol triggers endoplasmic reticulum stress by promoting phosphorylation of PERK and its downstream effector eIF2α, leading to suppressed translation of TFAP2C—a transcription factor critical for endothelial function. Further analysis revealed that TFAP2C directly binds to the VEGFA promoter to activate its transcription, thereby facilitating VEGFA/VEGFR2-dependent angiogenesis. Together, these findings not only broaden the understanding of propofol’s pharmacological profile, but also identify TFAP2C as a novel transcriptional regulator of VEGFA, offering new perspectives for therapeutic targeting of VEGFA-mediated angiogenesis.

Graphical abstract

Schematic representation of the mechanism of propofol inhibition of VEGFA/VEGFR2-associated angiogenesis via the PERK/eIF2α/TFAP2C axis.

The significance of cholesterol metabolism in cancer is a topic of renewed interest. Cholesterol is an essential factor for mammal cells, for it is not only involved in constituting the cell membrane, but also serves as a precursor to steroid hormones and bile acids. Numerous studies have provided increasing evidence of its high relevance to cancer progression. Targeting cholesterol metabolism by using cholesterol metabolism inhibitors has offered another therapeutic strategy for reversing drug resistance in tumors. Here, the regulatory process of cholesterol homeostasis under normal physiological conditions was introduced. Then, the mechanism by which cholesterol metabolism disorder caused gynecologic cancer development and therapy resistance was summarized. Finally, the therapeutic strategies targeting cholesterol metabolism were also discussed in this review.

The pathogenesis of atherosclerosis (AS) is a chronic disease marked by inflammation, and there are intimate associations with various forms of programmed cell death (PCD). Recently, the mechanisms of pyroptosis and autophagy in AS have attracted much attention. Pyroptosis is a form of PCD mediated by inflammasomes, which worsens local inflammatory responses by releasing proinflammatory factors (e.g., IL-18 and IL-1β) and favors plaque instability and thrombosis. Autophagy is a process that helps to keep cells healthy by breaking down damaged cell structures and abnormal proteins. Mitophagy, a specialized form of autophagy, is of major importance to redox homeostasis and the regulation of inflammation. However, the dysregulation of autophagy may disturb the cellular homeostasis, which then accelerates the progression of AS. Studies have found a complex mutual regulation between pyroptosis and autophagy. Autophagy can block the occurrence of pyroptosis by degrading the components of such as NLRP3. The inflammatory mediators released during pyroptosis may cause the disorder of autophagy, which aggravates the cell death and inflammatory response. The disorder of autophagy will also promote pyroptosis’ occurrence and progress. Both of them play a vital role in AS. This study is mainly focused on clarifying the relationship and molecular mechanism between pyroptosis and autophagy in the context of AS. These findings pave the way for new avenues for understanding its pathogenesis and potentially therapeutic decision-making.

Autism spectrum disorder (ASD) involves neuroinflammation and dysregulated neuronal death but lacks objective diagnostic biomarkers. This study investigated whether cell death could serve as a molecular basis for ASD diagnosis. We identified cell death-associated genes (CDGs) in peripheral blood mononuclear cells between ASD and control groups and performed functional enrichment, protein–protein interaction, immune characteristics, and non-negative matrix factorization clustering analyses. Key genes were further selected using 6 machine learning algorithms and weighted gene co-expression network analysis to construct a diagnostic model, which was subsequently validated using external human blood samples and mice prefrontal cortex samples. We explored microRNAs (miRNAs), transcription factors (TFs), and drugs potentially interacted with the key genes. Fourteen CDGs and 4 out of 22 types of immune cells were differentially expressed between ASD and controls in GSE18123. These genes were enriched in pathways such as neuron apoptosis and RAGE receptor binding. Among 6 machine learning models, K-Nearest Neighbors (KNN) model exhibited the best performance. Six key genes were selected as the most important hub genes and used to construct the diagnostic model. The model showed AUCs of 0.722 in GSE42133, 0.781 in our local samples, and 0.889 in mice prefrontal cortex samples. A total of 172 miRNAs, 111 TFs, and 98 drugs were found to interact with these key genes. The expression patterns of CDGs in the peripheral blood of children with ASD demonstrate potential diagnostic value. Further studies are warranted to validate their diagnostic performance in real-world settings and to elucidate the role of cell death dysregulation in ASD.

Background

Flap transplantation is a widely used for wound reconstruction but continues to carry a substantial risk of postoperative necrosis. We evaluated the therapeutic effect of phillyrin for improving flap survival and elucidated its underlying pharmacological mechanisms.

Methods

In vivo, a McFarlane flap model was established on the dorsal skin of rats. Animals were assigned to four groups: control, low-dose (17.5 mg/kg/day, intraperitoneal [i.p.]), medium-dose (35 mg/kg/day, i.p.), and high-dose (70 mg/kg/day, i.p.) phillyrin. At 7 days postoperatively, we evaluated flap survival, blood perfusion, oxidative stress, cytokine expression, toll-like receptor 4/nuclear factor κB/NOD-like receptor protein 3 (TLR4/NF-κB/NLRP3) axis activity, and pyroptosis. In vitro, human umbilical vein endothelial cells were treated with hypoxia/reoxygenation or lipopolysaccharide/nigericin models, to investigate the protective effects of phillyrin against inflammation-related pyroptotic injury.

Results

Phillyrin improved flap survival, significantly enhanced local blood perfusion, reduced neutrophil infiltration, and mitigated oxidative stress. Its mechanism of action is closely associated with the inhibition of the TLR4/NF-κB/NLRP3 axis: phillyrin significantly downregulated pathway activity, reduced cytokines secretion, and decreased the expression of pyroptosis-related effector proteins. In vitro, phillyrin demonstrated anti-inflammatory and anti-pyroptotic cytoprotective effects in H/R and inflammatory injury models by modulating the TLR4/NF-κB/NLRP3 axis.

Conclusion

Phillyrin improves flap survival by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway, suppressing excessive inflammation and alleviating ischemia-reperfusion injury.

Graphical abstract

Cardiac dysfunction in elderly diabetes, due to superimposition of age-related myocardial senescence and diabetes-induced injury, lacks effective therapeutic strategies. Ferroptosis may be a key mechanism underlying cardiomyocyte injury in diabetic cardiomyopathy. Mesenchymal stem cells (MSCs) and their exosomes show potential for repairing cardiomyocytes, restoring cardiac function, improving insulin sensitivity, and mitigating diabetes-related complications, but their mechanisms and relationship with ferroptosis remain unclear. The present study aimed to investigate reparative effects and ferroptosis-mediated mechanism of exosomes derived from VCAM-1 high-performance MSCs on aged diabetic cardiomyocyte injury. High-glucose-damaged senescent cardiomyocyte and aged rat model of diabetic cardiomyopathy were established and treated with VCAM-1⁺-UC-MSCs or -derived exosomes. Assessments of cell phenotypes, RNA sequencing, cardiac function, and markers of senescence and ferroptosis revealed significant mitochondrial damage, iron-ion accumulation, reactive oxygen species (ROS), and cardiac troponin (c-TnT) elevation in the damaged myocardial cells and rat heart tissues, along with weakened cardiac function and pronounced senescence and ferroptosis features, and activation of Ras/Raf/MEK/ERK/c-FOS pathway. VCAM-1⁺ MSCs or exosome administration significantly alleviated these effects, and improved cardiac function. Notably, the reparative effect of VCAM-1⁺-UC-MSCs-derived exosomes was superior to that of conventional MSCs-derived exosomes. In conclusion, VCAM-1⁺-UC-MSCs-derived exosomes attenuate cardiomyocyte ferroptosis by suppressing Ras/Raf/MEK/ERK/c-FOS pathway, thereby ameliorating myocardial injury resulting from superimposition of aging-caused myocardial senescence and diabetes-induced damage in elderly diabetic cardiomyopathy. This may lay a foundation for identifying potential prevention and treatment strategies and targets of MSCs and -derived exosomes on myocardial injury.

Trimethylamine N-oxide (TMAO) is linked to the onset and progression of acute pancreatitis (AP). Qingyi decoction (QYD) is widely used in Chinese hospitals for treating AP and its complications. This study aimed to explore the role and mechanism of QYD in alleviating severe acute pancreatitis-associated lung injury (SAP-ALI) by the modulation of the gut microbiota metabolite TMAO. The composition of the QYD was analysed using LC–MS/MS. A lung injury model in rats with SAP was created with a retrograde injection of 5% sodium taurocholate (STC, 50 mg/kg) into the pancreaticobiliary duct. The effects of exogenous TMAO, 3,3-dimethyl-l-butanol (DMB), and QYD on pulmonary microvascular endothelial barrier damage in SAP rats were assessed by ELISA, haematoxylin and eosin staining, transmission electron microscopy, RT‒qPCR, immunohistochemistry, and Western blot analysis. An in vitro model of TMAO-induced damage in HUVECs and a monocyte‒endothelial cell coculture system were created. RNA sequencing (RNA-seq) was employed to determine the impact of TMAO on the gene expression profile of endothelial cells. RT‒qPCR, Western blotting, flow cytometry, TUNEL assays, PI staining, and immunofluorescence were performed to assess whether TMAO induces endothelial cell PANoptosis and the effects of QYD on this process. The critical role of high mobility group box 1 (HMGB1) was investigated using a rescue experiment. The results demonstrated that QYD significantly alleviated pancreatic inflammation and lung injury in SAP rats, reduced TMAO levels, and effectively inhibited HMGB1-mediated pulmonary endothelial dysfunction during SAP. RNA-seq, scRNA-seq analysis and in vitro experiments confirmed that TMAO induced PANoptosis in endothelial cells. Mechanistically, QYD may exert protective effects on SAP-ALI by suppressing the TMAO-HMGB1 pathway that mediates endothelial cell PANoptosis, suggesting a potential therapeutic strategy for SAP.