Apoptosis-related Genes Research Articles

Apoptosis occupies a core position in the pathogenesis of multiple organ dysfunction syndrome (MODS). Therefore, exploring key mechanisms of action of apoptosis-related genes (ARGs) in MODS will play a positive and promoting role in the diagnosis and treatment of MODS. We obtained MODS-related data from public databases, and analyzed the disparately expressed genes between MODS and controls, as well as the weighted gene co-expression network analysis (WGCNA) genes most related to MODS. The intersection with ARGs was then used to obtain candidate genes. After that, by combining Cytoscape software, machine learning algorithms with expression verification, key genes were obtained, and a nomogram model was constructed and evaluated. Next, centering on key genes, gene set enrichment analysis, immune infiltration analysis, small ubiquitin-like modifier (SUMO) analysis, regulatory network construction, and drug prediction were carried out. At last, the expression of key genes in clinical samples was validated. After screening, S100A9, S100A8, and BCL2A1 were identified as the key genes of MODS. They were all significantly highly expressed in MODS and jointly participated in "oxidative phosphorylation" signaling pathway. The nomogram constructed based on the key genes had excellent predictive ability. There were 15 types of differentially infiltrated immune cells between MODS and controls, and they were correlated with the key genes. In addition, each of the key genes had two or more SUMOylation sites, and multiple miRNAs (hsa-let-7d-5p) and lncRNAs (XIST) were predicted. Subsequently, the key genes also jointly predicted potential drugs (curcumin). Finally, in clinical samples of MODS, the key genes also showed high expression. S100A9, S100A8, and BCL2A1 were the key genes of MODS in terms of apoptosis. The constructed nomogram had an excellent predictive value. It offers a novel approach and potential targeted therapy for the clinical diagnosis and treatment of MODS.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer and remains a clinical challenge due to its frequent resistance to therapy and poor prognosis in advanced stages. Apoptosis, a fundamental tumor-suppressive mechanism, exhibits paradoxical roles in cancer, wherein apoptotic tumor cells can also contribute to immunosuppression and tumor progression. However, the spatial dynamics, transcriptional heterogeneity, and prognostic relevance of apoptosis-related gene programs in ccRCC remain poorly defined. We performed an integrative analysis combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and summary-based Mendelian randomization (SMR) to dissect apoptosis-related malignant cell states in ccRCC. Cancer cells were stratified based on apoptosis gene signatures and CASP9 expression. Cell-cell communication was assessed using CellChat and spatial interaction networks were constructed using RCTD and mistyR. SMR was employed to link genetically regulated CASP9 expression with renal cancer risk. A CASP9-associated prognostic model was developed using LASSO Cox regression and DeepSurv on TCGA and E-MTAB-1980 cohorts. We identified transcriptionally and spatially distinct apoptosis-high and apoptosis-low malignant cell subpopulations. Apoptosis-high tumor cells, characterized by elevated CASP9 expression, preferentially localized near macrophage-enriched stromal regions and exhibited stronger spatial clustering. Ligand-receptor modeling revealed directional signaling via the SPP1-CD44 axis between CASP9-high cancer cells and macrophages. SMR analysis provided genetic evidence supporting CASP9 as a causal gene for renal cancer. CASP9-high cells demonstrated distinct developmental trajectories and formed multicellular spatial modules with macrophages and cycling cells. A five-gene apoptosis-related signature derived from CASP9-stratified tumor cells robustly predicted patient survival across both training and validation cohorts. Low-risk patients exhibited enriched immune infiltration, increased immune checkpoint expression, and enhanced immune pathway activity. Our study reveals that apoptosis, particularly CASP9-driven programs, defines a spatially organized, immunosuppressive malignant cell state in ccRCC. CASP9 acts as both a genetic driver and spatial regulator of tumor-macrophage interactions, contributing to disease progression. The CASP9-associated risk model demonstrates strong prognostic utility and highlights apoptosis as a promising therapeutic axis in ccRCC.

Objective Sepsis-induced cardiotoxicity (SIC) is a critical complication characterized by inflammation, oxidative stress, and apoptosis, leading to myocardial dysfunction. The short-acting opioid analgesic remifentanil (REMI) possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the cardioprotective effects of REMI on lipopolysaccharide (LPS)-induced SIC by examining inflammation, oxidative stress, apoptosis, and mitochondrial function. Materials and methods Thirty-two female Wistar albino rats were divided into four groups: control, lipopolysaccharide (LPS), LPS + REMI, and REMI. Myocardial and aortic tissues were analyzed for histopathology, immunoexpression of Caspase-3 (Cas-3), nuclear factor kappa beta (NF-κB), and tumor necrosis factor alpha (TNF-α). Oxidative stress markers, including total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), were measured. Mitochondrial apoptosis-related gene expression of AMP-activated protein kinase (AMPK), BCL2 Associated X (BAX), B-cell lymphoma 2 (BCL-2), Sirtuin 1 (SIRT1), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was assessed. Results LPS administration induced severe histopathological damage, increased oxidative stress (elevated TOS and OSI), and upregulated apoptotic (Cas-3, BAX/BCL-2 imbalance) and inflammatory (NF-κB, TNF-α) markers. REMI treatment significantly alleviated myocardial and aortic injury, reducing the histopathological score. It markedly decreased Cas-3, NF-κB, and TNF-α expression, lowered TOS and OSI levels, and modulated the BAX/BCL-2. Furthermore, REMI restored the expression of AMPK, SIRT1, and PGC-1α genes, indicating a protective effect on mitochondrial biogenesis and energy metabolism. Conclusions REMI exhibits significant cardioprotective effects in LPS-induced SIC by attenuating inflammation, oxidative stress, and apoptosis while preserving mitochondrial homeostasis.

To explore the molecular mechanism of hair follicle apoptosis in the goat hair cycle, single-cell transcriptome sequencing was performed on 8,214 hair follicle cells in the Anagen period, Catagen period, and Telogen period. We identified nine cell types and found that Matrix cells (MCs) enriched the Wnt signaling pathway and apoptosis-related genes. Further studies revealed the key dynamic genes (such as KRT19, API5) and regulatory factors (such as MSX2, LEF1) that determine the fate of MCs. This study mapped a high-resolution cell map of goat hair follicle apoptosis, providing new insights and diagnostic biomarkers for programmed cell death.

This study investigates the regulatory role of circFBN1 in chicken follicular granulosa cells (GCs) and its underlying molecular mechanisms through the miR-206/E2F5 pathway. circFBN1 was found to significantly enhance GC proliferation and inhibit apoptosis, as evidenced by increased expression of proliferation-related genes (PCNA, CDK1, and CCND1) and decreased expression of apoptosis-related genes (Caspase-3). Additionally, circFBN1 overexpression promoted the secretion of estradiol (E2) and progesterone (P4) by upregulating steroidogenesis-related genes (StAR and CYP11A1). Mechanistic studies revealed that circFBN1 functions as a molecular sponge for miR-206, thereby alleviating its inhibitory effect on the target gene E2F5. Dual-luciferase reporter assays confirmed the specific binding between circFBN1 and miR-206. Overexpression of miR-206 had the opposite effects, inhibiting GC proliferation, inducing apoptosis, and reducing E2 and P4 secretion by downregulating StAR and CYP11A1. Furthermore, E2F5 was identified as a direct target of miR-206, and its knockdown significantly reduced GC proliferation, increased apoptosis, and decreased steroid hormone secretion. These findings elucidate the regulatory mechanisms of the circFBN1/miR-206/E2F5 axis in avian follicle development and provide potential molecular targets for improving poultry reproductive performance. Future research should focus on exploring the upstream regulators of this axis and its interactions with other signaling pathways.

Oligoasthenozoospermia (OAS) is a major cause of male infertility, with limited effective treatments. Chinese patent medicine Zuogui Wan (ZGW) has been traditionally used to improve sperm quality, but its molecular mechanisms remain unclear. This study integrates network pharmacology, molecular docking, molecular dynamics (MD) simulation, and in vivo and in vitro experiments to explore ZGW’s therapeutic effects in OAS. Active compounds and targets of ZGW were identified using network pharmacology, and intersecting OAS-related targets underwent enrichment and protein-protein interaction (PPI) analysis. Molecular docking and MD simulations assessed compound-target binding affinity and stability. In vitro, CCK-8 assays measured cell proliferation, while qPCR and Western blot analyzed key gene and protein expression. In vivo, a rat OAS model was used to evaluate ZGW’s therapeutic effects through transmission electron microscopy (TEM), hematoxylin & eosin (HE) staining, and TUNEL assays. The expression of key molecular targets was further validated by qPCR and Western blot. A total of 182 potential targets were identified, with TP53, NF-κB1, and PKC as key hub genes. KEGG pathway analysis highlighted the involvement of the PI3K-AKT and MAPK signaling pathways.Four core bioactive compounds—Cyasterone, Betavulgarin, Kaempferol, and Quercetin—were identified, with Cyasterone exhibiting the strongest binding affinity and highest stability.In vitro experiments demonstrated that ZGW significantly promoted cell proliferation and regulated apoptosis-related gene expression, indicating its potential in enhancing sperm function. In vivo, ZGW improved testicular structure, enhanced sperm quality, and reduced spermatogenic cell apoptosis, as evidenced by TEM, HE, and TUNEL assays. Molecular validation further confirmed ZGW’s modulation of key signaling pathways involved in OAS. ZGW modulates apoptosis, oxidative stress, and key pathways (PI3K-AKT, MAPK) while regulating TP53, NF-κB, and PKC expression. Cyasterone exhibits strong binding and stability with core targets. This study supports ZGW as a potential treatment for male infertility.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-22348-w.

The widespread use of pesticides such as deltamethrin (a pyrethroid) and acetamiprid (a neonicotinoid) has sparked concerns regarding their effects on human health, particularly their potential role in carcinogenesis. This study investigated the cytotoxic, molecular, and functional effects of these pesticides, individually and in combination, on the MDA-MB-231 triple-negative breast cancer (TNBC) cell line. This model was chosen to specifically investigate estrogen recpetor (ER)-independent mechanisms due to its expression of targets such as aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptor gamma (PPARγ), and G protein-coupled estrogen receptor (GPER); however, it does not reflect normal mammary cell responses. Cytotoxicity was assessed via XTT assays, migration was analyzed using wound-healing assays, and gene expression changes in AhR, PPARγ, and Caspase-3 were measured using RT-qPCR. Molecular docking was performed to predict pesticide-protein interactions, and in silico toxicity assessments using ProTox-II supplemented the in vitro results by predicting toxicity profiles relevant to public health. Both pesticides exhibited dose-dependent cytotoxicity, and their combination produced an additive effect on cell viability. Importantly, suppression of cell migration and downregulation of AhR and PPARγ expression reflected toxic stress responses at high pesticide concentrations, rather than therapeutic or anti-cancer potential. While apoptosis-related gene expression (Caspase-3) was increased, this effect did not reach statistical significance. Molecular docking supported strong interactions with key pathways related to xenobiotic metabolism and apoptosis. These findings emphasize that, at high and non-environmentally relevant concentrations, deltamethrin and acetamiprid induce additive cytotoxic effects and disrupt molecular processes in a mechanistic cancer model. The results highlight the need for further investigation using normal cell systems and environmentally relevant exposures to clarify real-world risk and biological mechanisms, and should not be interpreted as evidence of therapeutic activity. This study underscores the mechanistic relevance of pesticide exposure in environmental toxicology rather than any potential therapeutic application.

Background: The accelerated lifestyle of modern society has increased reliance on processed foods preserved with synthetic additives. Although these substances effectively extend shelf life, several studies have raised concerns about potential adverse effects, suggesting that excessive or long-term exposure may interfere with essential cellular processes, including apoptosis. Objectives: This study aimed to investigate the impact of three widely used synthetic food preservatives; sodium benzoate (SB), potassium sorbate (PS), and sodium metabisulfite (SMB) on apoptosis-related gene expression in the human hepatocellular carcinoma cell line (HepG2). Methods: HepG2 cells were exposed to five increasing concentrations (6.25, 12.5, 25, 50, and 100 mg/L) of SB, PS, or SMB for 24 and 48 h. The transcriptional changes of key apoptotic genes (CASP3, CASP8, BAX, and BCL2) were quantified by real-time quantitative reverse transcription PCR (RT-qPCR) to evaluate their potential effects on intrinsic and extrinsic apoptotic pathways. Results: SB and PS induced dose-dependent transcriptional changes in apoptosis-related genes. Both preservatives upregulated BAX and downregulated BCL2, indicating an intrinsic pathway response, while simultaneously decreasing CASP3 and CASP8 expression associated with the extrinsic pathway. In contrast, SMB did not cause significant gene expression changes. Conclusions: SB and PS induced concentration- and time-dependent transcriptional alterations in apoptosis-related genes in HepG2 cells. In contrast, SMB did not elicit significant gene expression changes under the same conditions. These gene-level modulations were most evident at higher concentrations, which exceed typical dietary exposure levels. Therefore, while SB and PS were associated with transcriptional alterations at higher, experimentally relevant concentrations, additional research using primary human hepatocytes is needed to determine whether similar patterns occur in normal liver cells under physiological exposure conditions.

Intra-testicular injection of titanium dioxide nanoparticles induces chemical castration in male mice.

Investigating the process of apoptosis in HepG2 cells treated with palmitate, oleate, and palmitate/oleate combination.

Juvenile hormone signaling regulates apoptosis mediated chlorantraniliprole sensitivity in Spodoptera frugiperda (Lepidoptera: Noctuidae).

Microbial dysbiosis and hepatic inflammation under combined pesticide exposure: Insights into gut-liver axis disruption in Japanese medaka.

Cisplatin resistance significantly limits the effectiveness of chemotherapy in esophageal squamous cell carcinoma (ESCC). Understanding the molecular mechanisms driving resistance is essential for improving treatment outcomes. This study aimed to investigate the role of the FOXK1/AKT2 axis in cisplatin resistance in ESCC cells and to evaluate the potential of triptonide in reversing this resistance. Cisplatin sensitivity was assessed in ESCC cell lines with altered FOXK1 expression. A cisplatin-resistant TE1 cell line (TE1-R) was established by prolonged low-dose cisplatin exposure. Luciferase reporter assays were conducted to determine whether FOXK1 activates AKT2 transcription. Cell viability, colony formation, apoptosis assays, and expression analysis of apoptosis-related genes were performed to examine the effects of FOXK1, AKT2, and triptonide. FOXK1 overexpression reduced cisplatin sensitivity in ESCC cells, while FOXK1 knockdown restored sensitivity in TE1-R cells. FOXK1 directly enhanced AKT2 transcription by binding to its promoter region. The FOXK1/AKT2 axis promoted cell proliferation and suppressed cisplatin-induced apoptosis. Triptonide treatment downregulated FOXK1 and AKT2 expression, inhibited proliferation, induced apoptosis, and sensitized ESCC cells to cisplatin in a synergistic manner. The FOXK1/AKT2 signaling axis contributes to cisplatin resistance in ESCC. Triptonide reverses resistance by inhibiting this axis, offering a promising strategy to enhance cisplatin efficacy in ESCC therapy.

Polystyrene microplastics (PS-MPs) are microplastic particles produced during plastic manufacturing and environmental degradation, accumulating over time and entering ecosystems through various pathways, ultimately affecting organisms and inducing toxic effects. Current research on the impact of PS-MPs on mammalian oocyte quality, along with potential preventive mechanisms and strategies to mitigate toxicity, remains limited. This study investigates the effects of antioxidant melatonin on oocyte quality in the presence of PS-MPs, focusing on their influence on oocyte meiotic maturation and embryonic developmental potential. PS-MPs at a concentration of 30 μg/mL significantly impaired first polar body extrusion and reduced the success rate of parthenogenetic activation of mature oocytes in vitro. Furthermore, exposure to PS-MPs exacerbated oxidative stress, mitochondrial dysfunction, apoptosis, and autophagy impairment. Additionally, PS-MPs exposure led to a reduction in antioxidant gene expression and an increase in apoptosis-related gene expression in porcine oocytes. Immunofluorescence assays revealed that PS-MPs may induce oxidative stress, mitochondrial damage, and inflammation through the NF-KB/Nrf2/JNK MAPK signaling pathway crosstalk. Further investigation demonstrated that melatonin supplementation alleviated the toxic effects of PS-MPs exposure, offering potential as a therapeutic approach for mitigating PS-MP-induced reproductive toxicity and preserving oocyte quality.

Triclosan induces spermatogenic damage via the oxidative stress-P53-apoptosis pathway in zebrafish.

BackgroundLung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), has high incidence and poor prognosis. Although anti-programmed cell death protein 1 (PD1) therapy and epidermal growth factor receptor (EGFR) inhibitors benefit some patients, many remain unresponsive. Genome-wide association studies (GWAS) can identify risk loci, while single-cell transcriptomics enables exploration of genetic variations and mechanisms in LUAD.MethodsWe integrated GWAS data from FinnGen, IEU OpenGWAS, and GWAS Catalog with single-cell and spatial transcriptomics from GEO to investigate LUAD genetics and pathology. GWAS analyses identified SNP loci, risk factors, LD Score, and SMR results, revealing a novel apoptosis-related locus, Serine/Threonine Kinase 24 (STK24) (SMR P < 0.05). Single-cell analysis identified STK24-positive epithelial cells (STK24posEpi) and their transcription factors (SCENIC), developmental trajectory (Monocle), and tumor microenvironment roles (CellCall). Spatial mapping (RCTD) and trajectory analysis (stlearn) were combined with cell communication (CellChat), spatial signal flow (Commot), and co-localization (Misty). Bayesian deconvolution linked STK24posEpi to TCGA-LUAD bulk transcriptomes, assessing overall survival (OS), immune infiltration, and clinical traits. A prognostic model (STK24SuperPC, mean c-index 0.61) was built using multiple machine learning algorithms to predict survival and immunotherapy response. Laboratory experiments tested STK24’s effects on LUAD cell proliferation and apoptosis.ResultsSTK24 was identified as a LUAD risk factor (pSMR < 0.05). STK24posEpi communicated with fibroblasts, endothelial cells, and others via MIF and PDGF pathways, and was associated with apoptosis (Importance > 0.5), metastasis (Importance > 2), DNA repair (Importance > 1), and DNA damage (Importance > 2). Located at the origin of the trajectory, STK24posEpi correlated with poor prognosis (HR > 0, P < 0.05) and reduced lymphocyte infiltration (Pearson’s r < 0, P < 0.05). STK24 overexpression enhanced LUAD cell proliferation, migration, and colony formation, while reducing apoptosis, increasing BCL-2 and Caspase-3, and decreasing Cleaved-Caspase-3 expression.ConclusionsSTK24, an apoptosis-related gene, promotes LUAD progression by enhancing proliferation and inhibiting apoptosis, with STK24posEpi interacting in the tumor microenvironment through PDGF and MIF pathways. These findings offer potential therapeutic targets and support personalized LUAD treatment strategies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07111-z.

Involution is not modified by exposure to benzophenone-3 during pregnancy and mammary gland differentiation.

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent and heterogeneous malignancy. Normal cells maintain their homeostasis through Anoikis, and tumor cells enhance their own invasion and migration by resisting Anoikis. The search for biomarkers of resistance to Anoikis in head and neck tumors could be helpful in evaluating the prognosis of patients as well as in finding therapeutic targets for HNSCC due to the lack of more definitive biomarkers in HNSCC. HNSCC cells were cultured in suspension, and HNSCC cells were found to undergo apoptosis after losing the support of ECM.LASSO-Cox regression analysis was applied to the TCGA-HNSC cohort to evaluate the prognostic value of apoptosis-associated genes, resulting in the construction of an apoptosis-related prognostic model (CTTN, PLAU, PLK1, BID, MAPK11, SPINK1, VEGFA, PIK3R2, CEACAM1, MAD2L1, SLCO1B3, TFDP1, SFRP1, SPP1, SPHK1). A risk score-based nomogram was developed to optimally predict survival in HNSCC patients. The role of the prognostic model gene CTTN in HNSCC apoptosis was validated via PI staining, IF, and WB. Knockdown of CTTN affected FAK expression levels in cells, reducing their anti-apoptotic capacity by impairing cytoskeletal formation. We validated CTTN function in HNSCC-PDOs. We analyzed the role of CTTN and its major subpopulations in pan-cancer and HNSCC. Silencing CTTN significantly suppressed growth in patient-derived organoids (PDOs) from HNSCC patients. CTTN was highly expressed in most tumors and predominantly detected in epithelial and fibroblast cells of HNSCC. This study established an association between ARGs and HNSCC. We developed a novel ARG-associated signature capable of predicting prognosis in HNSCC patients. Furthermore, we found that inhibiting the apoptosis-related gene CTTN suppresses the anti-apoptotic capacity of HNSCC. Results from HNSCC-PDOs suggest that CTTN may represent a key target for HNSCC invasion and treatment.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-21891-w.

Lung cancer remains one of the most common and lethal malignancies worldwide, with poor prognosis largely due to late-stage diagnosis and resistance to therapy. Emerging evidence indicates that long non-coding RNAs (lncRNAs) play critical roles in cancer development, metastasis, and treatment resistance. Particulate matter (PM), a major environmental pollutant and recognized Group 1 carcinogen, has been linked to lung cancer through mechanisms that may involve dysregulation of lncRNA expression. This study aimed to identify PM-responsive lncRNAs in lung cancer, and investigate their potential functional roles. Microarray analysis of lung cancer cell lines A549, H358, H292, and HCC827, exposed to PM10, revealed significant up-regulation of lnc-MTPAP-1. TUNEL staining confirmed that silencing of lnc-MTPAP-1 via siRNA resulted in increased apoptosis across all tested lines. Transcriptome analysis using next-generation sequencing showed that knockdown of lnc-MTPAP-1 altered the expression of apoptosis-related genes, with up-regulation of TNS4, MyD88, and IL6R, and down-regulation of CLPTM1L and EI24. These findings suggest that lnc-MTPAP-1 may exert anti-apoptotic effects in lung cancer cells, and be involved in pollution-induced cancer progression. Further research should explore the therapeutic potential of targeting lnc-MTPAP-1, and better understand the molecular impact of PM exposure on lung cancer pathogenesis.

This study reports a novel targeted cancer therapy platform based on luteolin-loaded mesoporous silica nanoparticles functionalized with folic acid (Lu-MSN-FA NPs). MSNs were synthesized via a CTAB-templated sol-gel process employing tetraethylorthosilicate (TEOS) in an ammonium hydroxide-catalyzed system at 45 °C, followed by surfactant removal through acidic methanol reflux. The resulting NPs were surface-modified with (3-aminopropyl) triethoxysilane (APTS) and conjugated with FA using EDC/NHS activation to enable selective receptor-mediated uptake in cancer cells. The characteristics of Lu-MSN-FA NPs were evaluated using dynamic light scattering (DLS) and field-emission scanning electron microscopy (FESEM), revealing uniform, spherical particles with a favorable size for cellular uptake. Luteolin was successfully incorporated into the functionalized MSNs, achieving an encapsulation efficiency of 83.10%. Release assays indicated a controlled and sustained release pattern under experimental conditions. In vitro studies on AGS, HT-29, A2780, and A2058 cell lines revealed concentration-dependent cytotoxicity, with the highest sensitivity observed in A2780 cells. Cytotoxicity assays revealed the concentration-dependent cytotoxic effect of Lu-MSN-FA NPs, particularly on A2780 cells, with an IC50 of 5.7 µg/mL. Annexin V-FITC/PI dual staining and DAPI assays confirmed apoptosis induction. At the same time, real-time PCR demonstrated significant modulation of apoptosis-related genes (caspase 9 and p21) along with reduced expression of the antioxidant enzyme SOD. The Lu-MSN-FA NPs also exhibited robust free radical scavenging activity, underscoring their dual therapeutic potential. These findings indicate the effective formulation and controlled release performance of Lu-MSN-FA NPs, emphasizing their promise as a targeted delivery system for enhanced cancer therapy.