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Results for “STAT3 Transcription Factor”

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PubMed2026

Identification of STK35L1 as a potential prognostic biomarker in breast carcinoma, and its expression exhibits high correlation with EGFR activity.

Breast cancer (BC) is the second most prevalent malignancy after lung cancer, and the life expectancy is still very low due to therapeutic resistance and tumor relapse. It is crucial to identify novel biomarkers that can serve as potential therapeutic targets. In TNBC, aberrant activation of EGFR has also been implicated in the development of drug resistance. STK35L1 is a critical regulator of diverse cellular processes, including apoptosis and DNA damage. Notably, STK35L1 promotes drug resistance and regulates glycolysis and apoptosis through AKT signaling. The oncogenic role of STK35L1 is established in various cancers, including osteosarcoma, colorectal cancer, and acute myeloid leukemia. However, its association in BC has not yet been explored. In this study, we found that STK35L1 was significantly upregulated in multiple cancers, and its higher expression was associated with poor survival outcomes in BC patients. STK35L1 was differentially upregulated across all BC subtypes. An association between EGFR and STK35L1 expression was observed in normal breast tissues but not in BC. Interestingly, compared with normal breast tissue, EGFR mRNA expression is downregulated in BC tissues, with the greatest downregulation in the luminal B subtype and the least in TNBC. Furthermore, EGFR inhibition with gefitinib increased STAT3 phosphorylation at Tyr-705, and STK35L1 and EGFR gene expression were significantly upregulated. These data suggest that EGFR-STAT3 signaling may regulate STK35L1 and EGFR expression. In conclusion, we report an association of STK35L1 and EGFR in BC, highlighting STK35L1 as a potential prognostic biomarker and therapeutic target.

Humans↗

PubMed2025

Systematic acupuncture explains acupuncture at Baihui (GV20) and Fengchi (GB20) targeting the inflammatory response to regulate migraine.

OBJECTIVE: To take Baihui (GV20) and Fengchi (GB20) targeting inflammatory response to regulate migraine as an example to describe a new method for studying the mechanism of stimulating acupoints. METHODS: The target information of Baihui (GV20) and Fengchi (GB20) was retrieved, and after intersection with migraine, Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and UniProt Keywords were used for functional enrichment. After selecting the main pathway, rats were selected and nitroglycerin was used for modeling, and the behavioral scores, inflammatory factors, heme oxygenase 1 (HMOX1), protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), phosphorylated extracellular signal-regulated kinase 1/2 (P-ERK1/ERK2) and other states of the rats in the acupuncture, twisting, and electroacupuncture groups were compared. RESULTS: A total of 135 Baihui (GV20) targets and 27 Fengchi (GB20) targets were collected. A total of 73 target information were obtained after the intersection of these targets in migraine. These 73 targets have three main pathways: hypoxia-inducible factor 1 (HIF-1) signaling pathway, signaling by interleukins and inflammatory response. The main targets in the pathway were verified and found that interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and HMOX1, AKT1, STAT3, P-ERK1/ERK2 can be regulated by Baihui (GV20) and Fengchi (GB20). CONCLUSION: Baihui (GV20) and Fengchi (GB20) can regulate migraine by regulating inflammatory factors and HMOX1, AKT1, STAT3, P-ERK1/ERK2 and other changes in HIF-1 signaling pathway, Signaling by Interleukins and Inflammatory response pathways. Based on systems biology and network pharmacology, and with the model of "acupoint-target-disease", explore the research methods of systematic acupuncture and moxibustion. We believe this is a usable research direction for exploring the mechanism of acupuncture stimulation.

Acupuncture Points↗

PubMed2026

Hyper-IgE syndromes in pediatrics: clinical spectrum, differential diagnosis, and management.

Hyper-IgE syndromes (HIES) are rare inborn errors of immunity (≈1 per million) caused by pathogenic variants in STAT3, DOCK8 or IL6ST. They present with very high serum immunoglobulin E (IgE), recurrent bacterial or fungal infections, eczema and characteristic organ involvement. The autosomal dominant STAT3-deficient form features early-onset eczema, “cold” abscesses, recurrent pneumonias with pneumatoceles and skeletal or dental anomalies. Autosomal recessive forms such as DOCK8 or PGM3 deficiency show a more severe phenotype with viral skin infections, allergy, asthma and increased malignancy risk. HIES should be suspected in children with IgE >2000 IU/mL plus recurrent sinopulmonary or skin infections, severe eczema, atypical viral infections or a National Institutes of Health Hyper-IgE Syndrome (NIH HIES) score >40. Differentiation from severe atopic dermatitis, asthma, eosinophilic disorders and parasitic infections is essential. Evaluation includes eosinophils, lymphocyte subsets, T-helper 17 (Th17) cell analysis and targeted genetic testing. Management involves antimicrobial prophylaxis, treatment of complications, dermatologic care and genotype-based hematopoietic stem cell transplantation (HSCT), which is curative in DOCK8 but less effective in STAT3 deficiency. Early genomic confirmation enables timely recognition, identification of red flags, and genotype-specific therapy to improve long-term outcomes.

Humans↗

PubMed2026

MicroRNA-155 modulates STAT3 signaling by targeting KPNA1 in chronic chorioamnionitis of human placenta.

Chronic chorioamnionitis (CCA) is a placental inflammatory lesion characterized by maternal T cell infiltration and trophoblast apoptosis, resembling allograft rejection. MicroRNA-155 (miR-155) is a central regulator of immune and inflammatory pathways, but its role in CCA remains unclear. This study investigated whether miR-155 contributes to the pathogenesis of CCA by targeting karyopherin α1 (KPNA1) and modulating STAT3 signaling in human trophoblasts. Placental tissues from 28 CCA cases and 16 gestational age-matched controls were analyzed for miR-155 expression using quantitative RT-PCR and in situ hybridization. Functional assays were conducted in Swan 71 trophoblast cells following miR-155 overexpression and siRNA-mediated KPNA1 knockdown. Microarray and qRT-PCR analyses identified gene expression changes, while western blotting and dual-luciferase reporter assays were conducted to evaluate STAT3 activity and direct target binding. miR-155 expression was significantly elevated in CCA fetal membranes. KPNA1 was identified as a direct target of miR-155, and its suppression reduced STAT3 phosphorylation and nuclear translocation. Dual-luciferase assays confirmed that miR-155 binds to the 3' untranslated region of KPNA1 mRNA, thereby inhibiting its translation. These findings suggest that miR-155 downregulates KPNA1, leading to inhibition of STAT3 signaling in trophoblasts, which may contribute to maternal-fetal immune dysregulation and trophoblast apoptosis in CCA. The miR-155-KPNA1-STAT3 axis may represent a potential therapeutic target in pregnancy-related inflammatory disorders.

Humans↗

PubMed2026

Anti-inflammatory activity of an IL-6 missense variant against crystal-induced inflammatory response.

Interleukin-6 (IL-6) has an important modulator effect on inflammation and immunity and is involved in the progression of nephrolithiasis (kidney stone). However, whether IL-6 genetic variants affect the pathogenesis of kidney stones remains unclear. The present study conducted a combined investigation of candidate gene-driven screening and systematic screening on whole exome sequencing data from 28 patients of calcium oxalate stones, identifying a non-synonymous single nucleotide polymorphism (SNP) rs13306435 in IL-6 as a candidate research locus, which was further validated using HRM genotyping in an expanded cohort comprising 241 cases and 229 healthy subjects. Western blotting and qRT-PCR were used to assess the effects of this variant on crystal-induced inflammation, while molecular dynamics simulation was employed to analyze structural alterations in the receptor binding complex. In individuals aged ≤40 years, the A allele of rs13306435 was nominally associated with a reduced risk of stone formation, but no association was observed for the whole population. This missense variant causes an aspartate-to-glutamate substitution (D/E), inhibiting calcium oxalate monohydrate (COM)-triggered JAK2/STAT3 activation and inflammatory responses. However, it decreased the binding energy of IL-6/IL-6R/gp130 complex by increasing hydrogen bonds and salt brigdge at remote interfaces, suggesting that enhanced receptor binding does not necessarily translate to increased downstream signaling. Although this variant is not associated with general stone susceptibility, it exhibits notable anti-inflammatory activity by attenuating COM-induced JAK2/STAT3 activation and may influence the progression of stones through this pathway. These findings provide new insights into the role of anti-inflammatory mechanisms in nephrolithiasis.

Humans↗

PubMed2026

MLL4 protects cardiomyocytes against ischemia-reperfusion injury through STAT3-mediated mitochondrial function.

Myocardial ischemia-reperfusion injury (MIRI) is an inevitable pathophysiological response during the revascularization process following myocardial ischemia. Despite its clinical significance, effective targeted therapies for MIRI remain an unmet medical need. Mixed-lineage leukemia 4 (MLL4), a member of the SET family of histone methyltransferases, exhibits particular methyltransferase action toward histone H3 lysine 4 (H3K4). This study establishes a protective role for MLL4 in MIRI pathogenesis. Utilizing cardiomyocyte-specific Mll4 knockout mice and an in vivo ischemia-reperfusion (I/R) model induced by left anterior descending coronary artery ligation, we observed significant upregulation of MLL4 expression in cardiac tissue following I/R. Genetic ablation of Mll4 in cardiomyocytes markedly exacerbated both acute and chronic phases of MIRI. In vitro, Mll4 knockdown in neonatal rat cardiomyocytes (NRCMs) amplified mitochondrial dysfunction and apoptosis under hypoxia/reoxygenation (H/R) conditions. Integrated analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) revealed that Mll4 deficiency induces a pronounced reduction in H3K4 monomethylation (H3K4me1) and histone H3 lysine 27 acetylation (H3K27ac) enrichment at the Stat3 genomic locus. Mechanistically, MLL4 functions as a transcriptional activator of Stat3 by depositing H3K4me1 and H3K27ac, thereby facilitating STAT3 transcription. This regulatory cascade ultimately governs STAT3-dependent mitochondrial homeostasis. Collectively, these findings identify MLL4 as a critical epigenetic regulator of MIRI and suggest its therapeutic targeting may offer a promising strategy for mitigating reperfusion injury.

Animals↗

PubMed2026

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

Humans↗

PubMed2026

Integrated network pharmacology, molecular docking, and experimental validation to reveal the potential mechanism of Ginsenoside Rg1 on chronic obstructive pulmonary disease.

Ginsenoside Rg1 (GS Rg1), a natural flavonoid exhibiting anti-inflammatory and antioxidant properties, holds significant potential for treatment chronic obstructive pulmonary disease (COPD). Nevertheless, the precise mechanisms underlying its therapeutic effects remain to be fully elucidated. This study aimed to explore the role and potential mechanism of GS Rg1 in the treatment of COPD using network pharmacology, molecular docking, and experimental validation.Targets related to GS Rg1 and COPD were screened from public databases, and the potential common targets were then imported into the STRING database to construct a protein-protein interaction (PPI) network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed to identify key signaling pathways. Molecular docking was employed to predict the binding interactions between GS Rg1 and core targets. A BEAS-2B cell model induced by lipopolysaccharide(LPS) and cigarette smoke extract(CSE) was used to explore the protective mechanisms of GS Rg1. Western blot analysis was conducted to validate the critical targets and pathways involved in the anti-COPD effects of GS Rg1. Network pharmacology analysis revealed 105 common targets between GS Rg1 and COPD. The EGFR/PI3K/AKT and EGFR/STAT3 signaling pathways were selected for further validation. GS Rg1 was demonstrated to effectively inhibit inflammation and mucus hypersecretion in vitro models of COPD. Western blot results showed that GS Rg1 treatment significantly downregulated the expression of proteins involved in the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathway, consistent with the network pharmacology findings. CSE/LPS exposure induces inflammation and oxidative stress in COPD by disrupting the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathways, and GS Rg1 significantly alleviates these effects, which may be partially through regulating the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathway.

Ginsenosides↗

PubMed2025

Based on network pharmacology, molecular docking, and validation experiments to investigate the active components and mechanisms of action of Tibetan Medog County Citrus medica L.: In antioxidant activity.

BACKGROUND: The antioxidant potential of citrus plants is closely related to their geographical origin, making it crucial to evaluate the natural antioxidant properties of Citrus medica L. (C. medica) from Medog County, Tibet. METHODS: This study systematically investigates the antioxidant mechanisms of C. medica using network pharmacology, molecular docking, and experimental assays. RESULTS: The antioxidant activity experiments showed that C. medica exhibits good bioactivity, and the fruit has better antioxidant activity than the leaves. Network pharmacology revealed 11 active components of C. medica with 1547 antioxidant-related targets. Key targets include TP53, IL6, AKT1, STAT3, and TNF. Gene ontology (GO) analysis identified 1419 biological process entries, 147 cellular component entries, and 306 molecular function entries. Kyoto Encyclopedia of Genes and Genomes analysis identified 212 antioxidant-related signaling pathways. The GO and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the targets are involved in cancer pathways, protein binding, enzyme binding, lipid metabolism, and atherosclerosis. Molecular docking demonstrated that the 11 active components of Medog C. medica exhibit binding energies with core targets TP53, IL6, AKT1, STAT3, and TNF generally less than -5 kcal·mol-1, indicating good affinity. CONCLUSION: This study identifies the excellent antioxidant activity of C. medica from multiple aspects and elucidates its potential antioxidant mechanisms, providing a theoretical basis for the development and application of C. medica as an antioxidant functional additive.

Molecular Docking Simulation↗

PubMed2026

Exploring the mechanism of Acanthopanax in treating vertigo: A network pharmacology and molecular docking study.

Acanthopanax has therapeutic efficacy against vertigo; however, the underlying mechanism remains unclear. This study aimed to elucidate the mechanism by which Acanthopanax treats vertigo through integrated network pharmacology and molecular docking techniques, and retrieved all target genes of Acanthopanax for vertigo treatment from July to October 2025. Vertigo-related target genes were subsequently identified from public databases, including GeneCards and Online Mendelian Inheritance in Man. The intersection between Acanthopanax-derived targets and vertigo-related targets was analyzed to identify candidate target genes. Using the STRING platform, we constructed protein-protein interaction networks for the identified candidate targets and mined the core functional modules within these networks. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on candidate targets via the clusterProfiler package. A carp bile poisoning-liver injury target-pathway network was constructed via Cytoscape 3.8.2 software, network topology analysis was conducted, and the core components and targets were screened. The results found that A total of 295 candidate targets for the treatment of vertigo caused by Eleutherococcus senticosus were identified. Pathway enrichment analysis revealed that Eleutherococcus senticosus treatment for vertigo may be closely associated with pathways related to IL-17, TNF, phosphoinositide 3-kinase (PI3K)-Akt, p53, HIF-1, and Forkhead box O signaling. The core targets for the treatment of A. senticosus vertigo include TP53, AKT1, STAT3, TNF, and JUN. Network pharmacology and molecular docking studies suggest that A. senticosus may treat vertigo by regulating targets such as JUN, TNF, AKT1, STAT3, and STAT3 through pathways such as the IL-17, TNF, phosphoinositide 3-kinase-Akt, p53, HIF-1, and Forkhead box O signaling pathways. These mechanisms warrant further investigation in future o and in vitro studies.

Molecular Docking Simulation↗

PubMed2026

Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.

Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel-Lindau-deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (EPAS1) that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1/STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.

Basic Helix-Loop-Helix Proteins↗

PubMed2025

Blockade of interleukin-6 (IL-6) signaling in dedifferentiated liposarcoma (DDLPS) decreases mouse double minute 2 (MDM2) oncogenicity via alternative splicing.

Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene IL6ST and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic MDM2 amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.

Proto-Oncogene Proteins c-mdm2↗

PubMed2026

Potential Involvement of the IL-6/STAT3/MMP12 Signaling Axis in DMSO-Mediated Anti-Fibrotic Effects in Experimental Silicosis.

This study aims to investigate the anti-inflammatory and anti-fibrotic effects of dimethyl sulfoxide (DMSO) in a mouse model of silicosis, thereby exploring its potential therapeutic value. A mouse model of silicosis was established by intranasal instillation, and DMSO treatment was administered via intraperitoneal injection. The experiment was conducted over a period of 1 month. Lung tissues were collected from all mice; a subset was subjected to transcriptomic analysis, and differentially expressed genes were identified using the limma package. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were conducted using ClusterProfiler to investigate gene functions and associated pathways. The remaining samples were subjected to histopathological assessment by hematoxylin and eosin staining (HE) and Masson's trichrome staining, while Western blot analysis was performed to validate transcriptomic results. This study suggests that DMSO may alleviate the fibrotic process in silicosis by modulating the IL-6/STAT3-MMP12 signaling axis. In the silica-induced silicosis mouse model, DMSO attenuated disease-associated weight loss and reduced collagen deposition. Transcriptomic analysis indicated that DMSO suppressed the activity of multiple fibrosis-related pathways and identified 51 key genes, including MMP12, which was significantly downregulated. Western blot analysis further confirmed reduced MMP12 expression, accompanied by markedly decreased levels of IL-6 and p-STAT3, suggesting the IL-6/STAT3 pathway may play a crucial role in regulating MMP12 expression. DMSO may attenuate inflammatory responses and pulmonary fibrosis in silicosis by inhibiting activation of the IL-6/STAT3 signaling pathway, thereby reducing MMP12 expression.

Animals↗

PubMed2026

Acupoint Selection Patterns and Potential Mechanisms of Acupuncture in Knee Osteoarthritis: A Combined Data Mining and Network Pharmacology Study.

OBJECTIVE: To identify the core acupoint prescription and Kellgren-Lawrence (K-L) grade-dependent compatibility patterns of acupuncture for KOA through complex network analysis, and to predict the potential molecular mechanisms underlying the core prescription via network pharmacology. METHODS: Literature was retrieved from PubMed, EMbase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and SinoMed (inception to September 3, 2025). Frequency, association rule, complex network, and K-L grade subgroup analyses were applied. Potential targets of the core prescription were identified via network pharmacology and intersected with disease targets from OMIM, Therapeutic Target, GeneCards, and DrugBank. A protein-protein interaction (PPI) network was constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential molecular mechanisms. RESULTS: We included 522 studies, yielding 582 prescriptions involving 123 acupoints. The core prescription comprised 24 acupoints, including Dubi (ST35), Neixiyan (EX-LE4), Liangqiu (ST34), Xuehai (SP10), Zusanli (ST36), Yanglingquan (GB34), Yinlingquan (SP9), among others. K-L subgroup analysis revealed ST35, GB34, SP9, and SP10 as universal core acupoints. The mild-to-moderate subgroup mainly used local acupoints, while the moderate-to-severe subgroup centered on ST35, with increased distal acupoint usage and higher degree values. Network pharmacology analysis identified 77 overlapping targets. Core targets included tumor necrosis factor (TNF), interleukin 6 (IL6), interleukin 1 beta (IL1B), tumor protein p53 (TP53), matrix metallopeptidase 9 (MMP9), signal transducer and activator of transcription 3 (STAT3), transforming growth factor beta 1 (TGFB1), caspase 3 (CASP3), and B-cell lymphoma 2 (BCL2), which were enriched in inflammation and immunity, cartilage metabolism, and tissue repair pathways. CONCLUSION: The core acupoint prescription for KOA features local acupoints combined with distal ones, exhibiting distinct patterns across K-L grades. Our computational findings suggest that core acupoints may potentially delay knee joint degeneration by synergistically regulating inflammation, cartilage metabolism, apoptosis, and tissue repair, although these predictions require experimental validation. These findings provide preliminary evidence and a theoretical basis for standardized clinical point selection and further mechanistic research.

KOA↗

PubMed2026

Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.

Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-κB, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.

Cancer Stem Cells (CSCs)↗

PubMed2026

Targeting RELA and STAT3 regulates TNFRSF10A-mediated apoptosis in a novel apoptosis-based prognostic model for clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal malignancy and remains a major cause of cancer-related mortality worldwide. Although advances in surgery, targeted therapy, and immunotherapy have improved outcomes for patients, reliable biomarkers for predicting prognosis remain limited. Therefore, robust gene-based prognostic models are urgently needed to improve risk stratification and guide individualized treatment strategies. METHODS: We developed a novel prognostic model integrating apoptosis and immune - related genes (AIRGs) to predict overall survival (OS) in patients with ccRCC. RESULT: Using Gene Set Enrichment Analysis (GSEA) combined with least absolute shrinkage and selection operator (LASSO) Cox regression, we identified 7 key prognostic genes, namely, CCR4, TNFRSF10A, TEK, TGFA, CD14, IFITM1, and SEMA3G, that collectively demonstrated strong predictive performance in TCGA cohort with c-index = 0.711. Functional enrichment analyses revealed that apoptosis, immune regulation, and multiple oncogenic signaling pathways were significantly associated with the risk score, highlighting the critical role of the tumor microenvironment in ccRCC progression. Transcription factor binding analysis based on the JASPAR database suggested that RELA and STAT3 with scores of 0.829 and 0.951, respectively are potential upstream regulators within the prognostic network, particularly influencing TNFRSF10A expression. External validation using the International Cancer Genome Consortium (ICGC) dataset confirmed the robustness of the prognostic model with c-index = 0.612 Furthermore, in vitro experiments demonstrated that RELA and STAT3 regulate TNFRSF10A-mediated apoptotic signaling in ccRCC cells, providing mechanistic support for the bioinformatic findings. CONCLUSION: This study establishes a biologically informed and clinically relevant prognostic framework for ccRCC. Our findings highlight the therapeutic potential of targeting the RELA/STAT3-TNFRSF10A axis and contribute to the advancement of precision medicine in ccRCC.

Humans↗

PubMed2026

Parietal Cortex Transcriptomics Refines Parkinson Disease GWAS Nomination and Highlights STAT3 as a Putative Upstream Glial Regulator.

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinson's Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

Journal Article↗

PubMed2026

Proteomic Profiling of Pulmonary Function and Cardiovascular Disease Risk in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Pulmonary function is linked to cardiovascular disease risk; however, the underlying mechanisms remain unclear. We aimed to identify protein biomarkers associated with pulmonary function and examine their impact on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and all-cause mortality. METHODS: Data from White and Black Americans in the Atherosclerosis Risk in Communities study (visit 2: N=11 354, mean age=57 years; visit 5: N=3517, mean age=75 years), a prospective cohort, were analyzed. Linear regression assessed associations between protein levels and pulmonary function measures, including forced expiratory volume in 1 second and forced vital capacity. The impact of the identified proteins on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and mortality was estimated using logistic regression and Cox proportional hazards models. Pathway enrichment and Mendelian randomization explored underlying biological functions and causal effects. RESULTS: Of 4766 proteins analyzed, 364 were cross-sectionally associated with forced expiratory volume in 1 second (and forced vital capacity (false discovery rate<0.05). Ninety-four and 270 proteins had concordant positive and negative effects, respectively. Five pathways related to pulmonary and cardiac function were enriched. Of the 364 proteins, 112 were linked to all 4 outcomes, where 86 were associated with increased risk (odds ratio/hazard ratio [OR/HR], 1.05-1.42) and 26 with reduced risk (OR/HR, 0.69-0.96). Six proteins (STAT3 [signal transducer and activator of transcription 3], MIC-1 [growth differentiation factor 15], apoA-II [apolipoprotein A-II], TPST1 [protein-tyrosine sulfotransferase 1], integrin a1b1 [integrin alpha-I: beta-1 complex], and BLC [C-X-C motif chemokine 13]) showed potential inverse causal effects on with forced expiratory volume in 1 second and forced vital capacity, and integrin a1b1 demonstrated consistent inverse associations with chronic obstructive pulmonary disease, coronary heart disease, and heart failure risks. CONCLUSIONS: Proteins associated with pulmonary function may influence CVD risk. Six proteins, including integrin a1b1, represent promising targets for future interventions.

Aged↗