Apoptosis最新文献

The involvement of gut microbiota in metabolic disorders, including gallstones, has been increasingly reported, mainly focusing on the study of gut bacteria. However, as a relatively small proportion of intestinal microorganisms, the homeostasis of fungi still plays an important role in maintaining the health of the body. Our study showed that compared with healthy volunteers, patients with gallstones showed intestinal fungal dysregulation, which was marked by increased fungal biodiversity and changes in composition. At the same time, patients with gallstones also showed changes in fungal-bacterial interactions. In order to determine the role of intestinal fungal dysbiosis in gallstone formation, we administered fluconazole (a broad-spectrum antifungal drug) to C57 mice on a lithogenic diet and found that the formation of gallstones in mice treated with fluconazole was reduced. We then gavaged mice with Rhodotorula mucilaginosa and discovered that it can promote gallstone formation. Further analysis, including liver metabolism determination, liver immunohistochemistry and immunofluorescence, revealed that intestinal fungi promoted liver neutrophil infiltration and neutrophil extracellular trap formation to aggravate gallstone formation. In addition, through liver transcriptome sequencing, we found that the effect of fluconazole on intestinal fungi may hinder the formation of gallstones by regulating multiple targets related to gallstones. In summary, our study determined the role of intestinal fungal disorders in promoting gallstone formation, and fluconazole can effectively inhibit gallstone formation.

Programmed cell death has evolved from the classical concept of apoptosis to a diverse repertoire that includes necroptosis, pyroptosis, ferroptosis, cuproptosis, paraptosis, panoptosis, and even the reversal process of anastasis. These pathways have transformed our understanding of health and disease, influencing oncology, neurodegeneration, cardiovascular biology, infection, and immunity. Reflecting this growth, Apoptosis has reached a record Impact Factor of 8.1 in 2024, underscoring both the rising impact of cell death research and the journal’s role as its central forum. This success reflects a community effort of authors, reviewers, and editorial board members, and highlights how programmed cell death continues to shape the future of biology and medicine.

Actin gamma 1 (ACTG1) encodes the cytoskeletal protein γ-actin and is overexpressed in various cancers. Cisplatin-based chemotherapy is the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, most patients eventually develop cisplatin resistance. The association between ACTG1 and cisplatin resistance remains unclear. In this study, we found that high expression of ACTG1 was associated with poor prognosis in NSCLC. Knockdown of ACTG1 promoted mitochondrial fragmentation via interaction with the fusion protein MFN2 and induced ferroptosis. Mechanistically, ACTG1 knockdown disrupted mitochondrial dynamics, elevated mitochondrial ROS, reduced glutathione (GSH) levels, and enhanced lipid peroxidation. This cascade significantly inhibited the growth of cisplatin-resistant NSCLC cells and sensitized them to cisplatin. Furthermore, the ferroptosis inducer RSL3 synergized with cisplatin to enhance ferroptosis and mitochondrial fragmentation, effectively sensitizing ACTG1-overexpressing cells both in vitro and in xenograft models. Our findings establish ACTG1 as a critical mediator of cisplatin resistance in NSCLC through regulation of mitochondrial integrity and ferroptosis. Targeting the ACTG1-MFN2 axis combined with ferroptosis induction represents a promising therapeutic strategy to overcome cisplatin resistance.

Renal ischemia–reperfusion injury (IRI) remains a critical obstacle to optimal renal transplant outcomes, driving acute graft dysfunction and long-term allograft failure. While ferroptosis—an iron-dependent form of cell death—has been linked to IRI pathogenesis, the role of lipocalin-2 (LCN2), a regulator of iron homeostasis and inflammation, in transplant-related renal IRI remains uncharacterized. Six murine IRI transcriptomic datasets (83 samples) were integrated using weighted gene co-expression network analysis (WGCNA) and differential expression profiling to screen for IRI-associated hub genes. Findings were validated in two human transplant cohorts (212 samples) via 113 machine learning algorithms, including logistic regression, random forest, and ensemble models. Single-cell RNA sequencing (GSE237429) was used to map gene expression to specific renal cell populations, while a murine warm IRI model evaluated the effects of LCN2 inhibition (ZINC00640089) on tubular injury, ferroptosis markers (MDA, GSH, Fe²⁺), and inflammatory cytokines (IL-6, TNF-α) across mild (50-minute) and severe (80-minute) ischemia subgroups. WGCNA identified 36 hub genes, with LCN2 emerging as a key node in ferroptosis and immune regulation pathways. A six-gene machine learning model, including LCN2, CLU, and SOX9, demonstrated robust predictive accuracy for IRI (AUC = 0.93). Single-cell analysis revealed elevated LCN2 expression in neutrophils and macrophages in IRI kidneys, correlated with increased immune cell infiltration. In vivo, LCN2 inhibition significantly reduced severe ischemia-induced tubular injury, suppressed lipid peroxidation (MDA), restored glutathione levels (GSH), and alleviated iron overload (Fe²⁺) and reactive oxygen species (ROS). Systemic inflammation was mitigated, with IL-6 and TNF-α levels significantly reduced. This study establishes LCN2 as a pivotal mediator of ferroptosis and immune dysregulation in transplant IRI. A machine learning-driven multi-omics approach provides a novel diagnostic framework, while the inhibition of LCN2 is shown to alleviate IRI-induced tissue damage in these models. These findings highlight the utility of integrative analytics in uncovering biological targets and offer new therapeutic avenues for improving kidney transplant outcomes.

Sodium butyrate (NaB), a major intestinal metabolite, has been suggested to protect against osteoporosis (OP). This study aimed to elucidate the mechanism by which NaB regulates ferroptosis in OP. An ovariectomy-induced mouse OP model was established, and treated with NaB or the ferroptosis inhibitor Fer-1. Bone mineral density, bone microstructure, bone formation and resorption, and ferroptosis markers were assessed. In vitro, mouse bone marrow mesenchymal stem cells (BMSCs) were treated with NaB and the ferroptosis inducer Erastin to evaluate osteogenic differentiation and ferroptosis. Phosphatase and tensin homolog (PTEN) acetylation was detected by co-immunoprecipitation, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was evaluated by Western blot, and acetylation sites by point mutation. The role of PTEN acetylation was further validated using the p300 inhibitor C646 in vitro and in vivo. NaB treatment enhanced bone formation, suppressed ferroptosis, and promoted osteogenic differentiation in OP mice, mimicking the protective effects of Fer-1. In BMSCs, NaB promoted osteogenesis by inhibiting ferroptosis. Mechanistically, NaB induced acetylation of PTEN at K125/K128, suppressing its phosphatase activity and activating the PI3K/AKT pathway, thereby reducing ferroptosis. C646 partially abolished these effects. NaB promotes PTEN acetylation at K125/K128 to activate PI3K/AKT signaling, thereby inhibiting ferroptosis and alleviating estrogen deficiency-induced OP. These findings highlight NaB as a potential epigenetic metabolic regulator of bone metabolism.

Lactate, the primary byproduct of glycolysis, has been established as a critical barometer of tumor microenvironment homeostasis and is implicated in tumor progression. Alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) have been identified as sensors of intracellular L-lactate and as contributors to cancer development. Nonetheless, investigations into the different roles of AARS1 and AARS2 across various cancer types remain lacking. In this study, we preliminarily explored the correlations between AARS1/2 and the tumor microenvironment in pan-cancer. We first examined the expression patterns of AARS1 and AARS2 across 33 cancer types. Subsequently, we analyzed the relationship of AARS1/2 with clinical features and mutational landscape utilizing the GSCA and cBioPortal databases. Survival outcomes associated with AARS1/2 were assessed through Cox regression and the Kaplan–Meier method. Additionally, we examined the correlations between AARS1/2 and drug sensitivity, as well as immune infiltration, using the GSCA database, TISIDB database, and the CIBERSORT algorithm, respectively. Notably, significant heterogeneity of AARS1 and AARS2 was observed across various dimensions, including expression profiles, clinical outcomes, mutation spectra, and immune infiltration. The expression patterns of AARS1/2 were statistically different in urologic neoplasms. Similarly, survival analysis revealed a close correlation between elevated AARS1 expression and unfavorable prognosis in patients with urologic neoplasms, while AARS2 expression level was not. Interestingly, the results of immune infiltration indicated the statistical heterogeneity of AARS1 and AARS2 in certain urologic neoplasms, especially in bladder urothelial carcinoma (BLCA). Specifically, (1) the correlation between AARS1/2 expression and immune-related scores in BLCA was opposite; and (2) TIDE analysis demonstrated that elevated AARS1 expression was related to a high TIDE score in BLCA, while AARS2 was not. Further detailed analysis of AARS1 and AARS2 in the context of immune infiltration and functional enrichment in BLCA may partially account for these observations. In conclusion, our findings highlighted the heterogeneity of AARS1 and AARS2 across various cancers. Based on our data, AARS1 was identified as a potential prognostic biomarker and a candidate for immunotherapy targeting in urologic cancers, though further validation is needed to confirm its clinical utility.

Astragaloside IV (AS-IV), a bioactive compound renowned for its anti-inflammatory, antioxidant, and anti-apoptotic properties, has not yet been investigated for its potential role in modulating cardiac function under high-altitude conditions. This study elucidates the cardioprotective effects of AS-IV against high-altitude-induced cardiac injury and explores the underlying molecular mechanisms. Under hypobaric hypoxia, we observed significant cardiac dysfunction, hypertrophy, and fibrosis, as confirmed by comprehensive echocardiographic, histopathological, and molecular analyses. Remarkably, AS-IV administration effectively attenuated these pathological changes, restoring cardiac architecture and function while mitigating oxidative stress and apoptosis. Further in vivo and in vitro experiments revealed that AS-IV preserves mitochondrial integrity by enhancing membrane potential, ameliorating mitochondrial impairment, and modulating calcium homeostasis through the calcium-sensing receptor (CaSR)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis. Network pharmacology-based screening identified key molecular targets, including epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mouse double minute 2 (MDM2), which were subsequently validated via molecular docking studies demonstrating strong binding affinities between AS-IV and these core proteins. Mechanistic investigations further revealed that siRNA-mediated EGFR knockdown or pharmacological activation of CaSR abolished AS-IV’s cardioprotective effects, including its anti-apoptotic, antioxidant, and mitochondrial-stabilizing properties. Taken together, our findings demonstrate that AS-IV exerts its therapeutic effects through a dual-pathway mechanism involving (1) the EGFR-PI3K-AKT-MDM2 axis and (2) CaSR-NF-κB signaling. These insights position AS-IV as a promising candidate for the prevention and treatment of high-altitude-related cardiovascular diseases.

Sepsis, a life-threatening condition, involves dysregulated cholesterol metabolism critical for immune regulation and cellular processes. This study employed multi-omics and machine learning to explore cholesterol metabolism in sepsis, aiming to identify novel therapeutic targets. Transcriptome and single-cell RNA sequencing data for sepsis were retrieved from the Gene Expression Omnibus (GEO) database. The limma package and WGCNA co-expression network were used to screen genes, hybridized with cholesterol metabolism genes (CMGs) to identify hub genes. Machine learning algorithms screened pivotal genes to construct diagnostic model, validating performance via multi-cohort Receiver Operating Characteristic (ROC) curve. Non-negative matrix factorization (NMF) based molecular typing using CMGs, and integration of 101 machine learning algorithms built prognostic models. Single-cell analysis characterized expression patterns of pivotal genes and key subsets. Causal effects and phenotypic associations of target genes were evaluated using Summary data-based Mendelian Randomization (SMR) and PheWAS. Integrated transcriptomic analysis identified three key genes (VDAC1, VDAC2, and LDLRAP1) associated with dysregulated cholesterol metabolism in sepsis. Machine learning-based diagnostic models exhibited high predictive accuracy. NMF clustering revealed two molecular subtypes, with Cluster 1 characterized by immunosuppression and metabolic reprogramming, linked to poorer prognosis. A machine learning model integrating 101 algorithms predicted 28-day mortality. The single-cell transcriptome atlas identified CD14⁺CD163⁺ monocytes as the hub cell population in the immune microenvironment of sepsis, and the active cholesterol metabolic pathway might constitute the core for regulating the immune response. Elevated VDAC2 expression was significantly correlated with reduced sepsis risk, as determined by SMR analysis. This study underscored cholesterol metabolism’s critical role in sepsis pathogenesis. Multi-omics nominates VDAC2 as a candidate protective locus in sepsis-associated cholesterol dysregulation.

Immune checkpoint inhibitors (ICIs) have shown promise in enhancing non-small cell lung cancer (NSCLC) patient prognoses, but their effectiveness is contingent upon the specific tumor microenvironment (TME). In this research, we examined the heterogeneity and plasticity of tumor-associated macrophages in lung adenocarcinoma (LUAD) using single-cell sequencing data GSE207422, identifying genes that may influence their polarization. We identified a positive correlation between BCAT1 expression in immune-resistant patient tissues and M2 macrophage infiltration. Pseudo-temporal analysis revealed a significant overlap between BCAT1 expression dynamics and the trajectory of macrophage M2 polarization. Evidence from both in vitro and in vivo studies indicated that BCAT1 might foster an immunosuppressive environment by driving M2 macrophage polarization, which could account for the aggressive spread of LUAD and suboptimal responses to immunotherapy. Overall, our findings flagged BCAT1-high-expressing macrophages as a suppressive element in the TME, hinting that targeting BCAT1 could shift macrophage polarization and enhance patient outcomes.

Neutrophil-mediated inflammation plays a crucial role in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Dysregulated neutrophil death has been implicated in promoting neutrophil priming and activation. PANoptosis, an inflammatory programmed cell death, participates in the development of various autoimmune diseases. The current study aims to identify the key PANoptosis-related marker and investigate its association with disease activity of AAV. Gene microarray data of patients with ANCA-associated glomerulonephritis (ANCA-GN) was downloaded from the Gene Expression Omnibus (GEO). PANoptosis-associated genes were sourced from GeneCards. The hub-marker of PANoptosis-related genes was identified by integrated bioinformatical analysis. The single-cell sequencing data from ANCA-GN mice were used to determine the location of hub genes. Then levels of activated CD11b on neutrophils from peripheral blood, as well as soluble CD11b in urine and plasma were measured in AAV patients. Their associations with clinicopathological parameters of AAV patients were subsequently analyzed. Co-localization of CD11b and neutrophils in renal specimens of AAV patients was evaluated by immunofluorescence staining. Changes of intracellular metabolic pathways of neutrophils from AAV patients were further investigated. A small molecule inhibitor was used to explore the effect of intracellular fatty acid metabolism (FAO) on neutrophil CD11b activation and PANoptosis. CD11B was identified as the pivotal PANoptosis-related gene in AAV by integrated bioinformatics analysis. The level of activated CD11b on neutrophils was significantly higher in active AAV patients compared with healthy controls, and elevated neutrophil CD11b levels positively correlated with disease activity, as evidenced by higher levels of hypersensitive C-reactive protein (hCRP), increased Birmingham Vasculitis Activity Score (BVAS), elevated serum creatinine levels at sampling and a higher proportion of cellular crescents in renal specimens of AAV patients. We also demonstrated the presence of neutrophil CD11b in renal specimen of AAV patients. Moreover, along with elevated Cd11b expression, neutrophils from ANCA-GN mice exhibited an aberrant FAO phenotype and a down-regulated peroxisome proliferators-activated receptor (PPAR)-α pathway, as compared with healthy controls. GW7647, a PPARα agonist, could alleviate AAV serum-induced neutrophil CD11b activation and PANoptosis. CD11B was a pivotal PANoptosis-related gene in AAV. The level of activated CD11b on neutrophils was associated with disease activity in AAV patients.