STAT3 Signaling Research Articles (Page 1)

Platycodin D targets ZNF70 to inhibit NLRP3 inflammasome and STAT3 signaling pathway to ameliorate colitis.

The development and stability of induced regulatory T cells (iTregs) are essential for their immunosuppressive function and therapeutic potential in inflammatory diseases. Although Treg-based immunotherapy offers promise for restoring immune tolerance, clinical application is limited by the instability and reduced potency of iTregs. STAT6 signaling has been implicated in destabilizing Foxp3 expression, a key marker of Treg identity. Here, we investigated the impact of pharmacological STAT6 inhibition on iTreg differentiation, stability, and function both in vitro and in vivo. Naïve CD4⁺ T cells were differentiated into iTregs under standard conditions or expanded with IL-2 in the presence of the STAT6 inhibitor AS1517499 (AS-iTregs). STAT6 inhibition enhanced iTreg stability, maintaining high expression of Foxp3, CD25, PD-1, and CTLA-4 for up to 10days, even in inflammatory conditions. AS-iTregs also showed increased mRNA levels of Foxp3, IL-10, TGF-β, and PD-1, and reduced IL-6, IL-1β, and DNMT1 expression-suggesting improved functional and epigenetic stability. In the DSS colitis model, adoptive transfer of AS-iTregs alleviated disease severity, preserved mucosal architecture, and increased goblet cell numbers. Histopathological analysis showed reduced epithelial damage and inflammation compared to controls. Importantly, AS-iTregs did not promote tumor growth in a colitis-associated cancer model. Furthermore, in vivo administration of AS1517499 during acute colitis enhanced Treg expansion, activation, and suppressive function. These findings establish STAT6 inhibition as a promising approach to boost iTreg stability and efficacy, advancing the potential of Treg-based therapies for inflammatory disorders.

Quercetin, a secondary metabolite derived from plants with both medicinal and edible values, has demonstrated potential in cancer treatment, including endometrial carcinoma. However, its anti-tumor effect on cancer stem-like cells (CSCs), a subpopulation considered to be a major driver of tumor recurrence and metastasis-remain largely unclear. This study aimed to evaluate the anti-tumor effects of Quercetin by targeting CSCs and suppressing their stemness properties. CSCs were enriched using serum-free medium and treated with a range concentration of Quercetin. The STAT3/JAK2 signalling was detected by western blot after treatment with Quercetin. The effects of Quercetin on malignant behaviours in CSCs, including proliferation, cell cycle distribution, spheres formation and invasion, were further assessed. Quercetin treatment inhibited the formation and maintenance of spheres derived from endometrial carcinoma cell lines EMN8 and EMN21.It also downregulated the expression of stemness markers, including ALDH1A1, c-Myc, Nanog, and Oct4.We further revealed that estrogen receptor α (ERα) is critical for mediating the inhibitory effects of Quercetin on stemness and malignant behavior, suggesting that ERα sensitizes CSCs to Quercetin. Quercetin suppressed STAT3/JAK2 phosphorylation and subsequently inhibited the transcriptional activity of STAT3's downstream target gene, Oct4.These inhibitory effects were reversed by the STAT3 activator Colivelin. Our findings demonstrate that Quercetin targets the stemness of CSCs in an ERα-dependent manner, highlighting its potential as a promising therapeutic agent against CSCs to improve clinical outcomes in endometrial carcinoma.

Inflammatory signaling, metabolic reprogramming, and stromal complexity have emerged as core hallmarks of pancreatic ductal adenocarcinoma (PDAC). Crosstalk between these programs could represent potential targets to concurrently perturb multiple tumor-promoting processes. By integrating multi-omics data from clinical cohorts, patient-derived organoids, and autochthonous models, we uncovered tumor-intrinsic inflammatory cascades in PDAC as master regulators of mevalonate pathway hijacking, which drove both malignant progression and stromal co-evolution. TNFSF13B+ tumor-associated macrophages activated STAT3 signaling in neoplastic epithelia, leading to the transcriptional upregulation of USP20. This deubiquitinase stabilized HMGCR to potentiate mevalonate flux, resulting in cholesterol and geranylgeranyl pyrophosphate overproduction. Stimulation of YAP/TAZ signaling induced by the USP20-mediated metabolic alterations promoted tumor cell proliferation and triggered the activation of cancer-associated fibroblasts (CAFs). Genetic ablation or pharmacological inhibition of USP20 using a selective inhibitor reversed tumor metabolic dysregulation, suppressing both tumor growth and stromal desmoplasia. Furthermore, the combination of USP20 inhibition and anti-PD-1/anti-CTLA-4 immunotherapy resulted in enhanced anti-tumor efficacy. These findings reveal the STAT3-USP20-HMGCR axis as a central coordinator of PDAC malignancy and position USP20 inhibition as a strategy to suppress oncogenic signaling, perturb metabolic reprogramming, and reverse microenvironmental remodeling.

Myocardial ischemia-reperfusion injury (MIRI) remains a major clinical challenge following revascularization for acute myocardial infarction. The multi-component, multi-target nature of traditional herbal formulas like HuangLian-4 (HL4) offers a promising therapeutic paradigm for this complex disease, yet its underlying molecular mechanism is poorly understood. This study aimed to systematically elucidate the cardioprotective mechanism of HL4 by integrating serum pharmacochemistry, network pharmacology, and systems biology with experimental validation. An in vitro MIRI model was established using a hypoxia/reoxygenation (H/R) protocol in H9c2 cardiomyocytes, and the effects of HL4 were assessed by ELISA, qRT-PCR, Western blot, and molecular docking. Our results demonstrate that HL4 treatment significantly attenuated H/R-induced cardiomyocyte injury and inflammation, reducing the release of CK-MB, LDH, IL-6, and TNF-α. Mechanistically, our primary finding revealed that HL4 markedly rescued the H/R-induced downregulation of the pro-survival factor STAT3 at both the mRNA and protein levels. This activation of STAT3 was accompanied by a significant increase in the anti-apoptotic protein Bcl-2 and a decrease in pro-apoptotic Bax, alongside the suppression of the maladaptive factor HIF-1α. These experimental findings were powerfully corroborated by systems-level bioinformatic analysis, which independently identified the STAT family as key upstream regulators of a MIRI-critical gene network. Furthermore, molecular docking confirmed a strong binding affinity between key active compounds of HL4 and the STAT3 protein. In conclusion, this study demonstrates that HL4 alleviates MIRI by activating the STAT3 signaling pathway, which in turn orchestrates a downstream anti-apoptotic program. Our findings provide a robust molecular rationale for the clinical use of HL4 and establish STAT3 modulation as a promising therapeutic strategy for MIRI.

Introduction: Pulmonary arterial hypertension (PAH) is a progressive and potentially fatal condition characterized by the continuous obstruction of the pulmonary arteries, which ultimately leads to right ventricular (RV) failure. Inflammation plays a crucial role in the development of PAH, with interleukin-6 (IL-6) contributing to vascular remodeling, the proliferation of smooth muscle cells, and fibrosis. Current therapeutic approaches for PAH primarily focus on promoting vasodilation. However, targeting inflammatory mechanisms could serve as a complementary strategy to improve treatment outcomes Hypothesis: We hypothesized that neutralizing IL-6 with species-specific antibodies inhibits the features of PAH in animal models. Methods: Rats in the monocrotaline and sugen/hypoxia mouse model were treated with IL-6 neutralizing antibodies (nAb). After the IL-6 nAb treatment, assessments were conducted that included cardiac magnetic resonance imaging (cMRI) to evaluate RV structure and function, hemodynamic measurements, and histological analyses of lung tissues. Western blotting was performed to assess IL-6/STAT3 and downstream signaling, while transcriptomic changes were analyzed using bulk RNA sequencing. Additionally, the findings were further evaluated in human primary endothelial cells. Results: IL-6 neutralizing antibody (nAb) treatment led to significant improvements in right ventricular (RV) structure and function, as demonstrated by cardiac MRI. Hemodynamic analyses revealed reductions in RV systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). Histological evaluations showed a decrease in smooth muscle proliferation and cardiomyocyte hypertrophy. Additionally, IL-6/STAT3 and FOXO downstream signaling were reduced, as indicated by Western blot analysis. The downregulation of genes related to hypertrophy, fibrosis, inflammation, and oxidative stress was further confirmed through RNA sequencing. Conclusion: These findings support the potential of IL-6-targeted therapies as a complementary therapy for PAH. Keywords: Pulmonary arterial hypertension, IL-6, STAT3, IL-6 neutralizing antibody, rodent models.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and core component of the polycomb repressive complex 2 (PRC2), is an important player in cancer progression through its powerful effects on chromatin remodeling and gene silencing. In addition to its classical role in regulating the cell cycle and tumor proliferation, numerous publications have identified the broad role of EZH2 in modulating the tumor immune microenvironment (TIME), leading to immune evasion and resistance to immunotherapy. EZH2 has been shown to silence immune surveillance genes by binding to H3K27me3 histone, leading to epigenetic silencing in lymphomas and thereby reducing tumor immunogenicity, which facilitates immune escape. EZH2 also modulates the recruitment and activity of immunosuppressive cells by epigenetically modifying cytokine and chemokine networks. Importantly, EZH2 upregulates PD-L1 expression either directly or indirectly through its pro-oncogenic activation of STAT3 signaling, which induces T cell exhaustion and ultimately resistance to checkpoint inhibitors in cancers such as breast cancer and glioblastoma. Furthermore, EZH2 also influences the regulation of immune-related microRNAs, including the suppression of the miR-144/451a cluster, which encourages immunosuppressive macrophage polarization. Pharmacological EZH2 inhibition has been shown to be an arm of a synergistic therapy, combining immune checkpoint blockade therapies, which can reinstate antigen presentation and T cell infiltration, highlighting EZH2 as an essential epigenetic modulator of tumor-immune interactions. It remains a viable target for therapy to overcome immune resistance and improve cancer immunotherapy outcomes.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), affecting approximately 1 in 500 individuals globally, is a leading cause of sudden cardiac death in young adults. Current treatments are largely symptomatic and fail to alter disease progression. This study addresses the critical need for disease-modifying interventions by elucidating molecular mechanisms underlying HCM and identifying therapeutic candidates through a drug repurposing strategy. METHODS: We employed a systems biology framework, integrating transcriptomic profiles from human HCM cardiac tissue with drug-response signatures from the Connectivity Map (CMAP) database to predict compounds capable of reversing disease-associated gene expression patterns. Atovaquone emerged as a top candidate. Its therapeutic efficacy was evaluated using in vitro and in vivo models, including established genetic HCM mouse models and cardiomyocyte hypertrophy assays. Target deconvolution and mechanistic analyses were conducted to define the molecular basis of its action. RESULTS: Atovaquone markedly ameliorated pathological features in HCM models, including reduced left ventricular wall thickness, heart weight-to-body weight ratios, myocardial fibrosis, cardiomyocyte size, and expression of hypertrophy markers (Nppa/Nppb). CETSA-based thermal proteome profiling identified the membrane-associated E3 ubiquitin ligase MARCH3 as a direct target of Atovaquone. This interaction was supported by molecular docking and validated by CETSA and DARTS assays. Functional studies demonstrated that MARCH3 knockdown abrogated Atovaquone’s anti-hypertrophic effects in phenylephrine-stimulated neonatal rat ventricular myocytes, evidenced by increased hypertrophic gene expression and cell size. Mechanistically, Atovaquone enhanced MARCH3-mediated polyubiquitination of GP130, facilitating its lysosomal degradation and suppressing STAT3 phosphorylation at Y705 and S727. The use of leupeptin, but not MG132, reversed GP130 downregulation, confirming lysosomal pathway specificity. CONCLUSION: This study identifies Atovaquone as a repurposed, disease-modifying candidate for HCM therapy. By targeting MARCH3 and inducing lysosomal degradation of GP130, it disrupts pathological STAT3 signaling. These findings provide both mechanistic insight and translational potential for a novel therapeutic approach in HCM.

Background/Objectives: Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of immune pathways and may hold diagnostic and therapeutic relevance in autoimmune diseases such as Multiple Sclerosis (MS). However, research on lncRNAs in MS remains fragmented and geographically clustered. This systematic review aimed to collate and critically evaluate studies of lncRNA expression in MS, assess consistency of findings across studies, and synthesize proposed functional implications of the most frequently studied lncRNAs. Methods: This PROSPERO-registered review (CRD420250575938), conducted in accordance with PRISMA, searched PubMed, Scopus, Embase, and Web of Science (2010–2024) for studies evaluating lncRNA expression in adult MS (≥18 years of age). Eligible studies included ≥20 participants and assessed lncRNAs in blood, PBMCs, serum, plasma, or CSF using qRT-PCR, RNA-seq, or microarrays. Pediatric, review, animal, and in vitro studies were excluded. Two reviewers independently screened and extracted data, with risk of bias evaluated using QUADAS-2. Results: Narrative synthesis of 51 studies identified 77 unique lncRNAs. A limited set (MALAT1, GAS5, MEG3, H19) demonstrated consistent dysregulation in MS, whereas others (THRIL, IFNG-AS1, HOTAIR, TUG1) exhibited context-dependent expression influenced by treatment, relapse status, or demographics. Functional annotations converged on immune pathways, including NF-κB, STAT3, IFN-γ/Th1, and glucocorticoid signaling. Conclusions: This review identifies reproducible and context-specific lncRNA dysregulation in MS, emphasizing the need for transcriptome-wide approaches, standardized methods, and multi-center validation. Current evidence is constrained by geographic clustering, preselection bias, and methodological heterogeneity.

Abstract Eliminating reactive oxygen species (ROS) and inducing anti‐inflammatory M2 macrophages polarization are crucial for tissue repair. However, precisely regulating these processes in vivo is highly challenging. Despite small biomolecules and metal ions with ROS scavenging and M2 polarization potential, their high solubility hindered precise delivery, limiting therapeutic efficacy. This study proposes an innovative strategy involving the nanoscale and solidification of these molecules and ions to create pH‐responsive chlorogenic acid‐zinc nanoparticles. Leveraging macrophage's endocytosis and lysosomal acidity, these nanoparticles trigger precise metal ions and small molecules storm within 3 h after internalization, which effectively scavenges ROS and repairs damaged mitochondria. Additionally, it specifically inhibits the phosphorylation of NF‐κB p65 while activating the STAT6 signaling pathway within macrophages. This dual action reprograms macrophages toward the M2 phenotype, restoring immune homeostasis in the wound microenvironment. Notably, zinc ions probe is utilize to observe the dynamic process of the zinc ions storm and employed a series of mitochondrial‐related probes and transmission electron microscopy to validate the underlying mechanism of macrophage reprogramming through mitochondrial repair. The meticulously designed experiments on diabetic wound repair in mice fully validate these mechanisms, offering a universally applicable nanomedicine design approach for macrophage regulation and tissue repair.

Integrative genetic, single-cell and mechanistic dissection identifies bisphenol a as a causal driver of preeclampsia via fibroblast-derived IL-6/STAT3 signaling.

Asiatic acid inhibits keloid fibroblast migration and collagen deposition via suppression of STAT3 activation.

Network pharmacology combined with experimental verification for exploring the potential antidepressant mechanism of Traditional Chinese Medicine Buyang Huanwu Decoction in lipopolysaccharide-induced depressed mouse model.

HMGB1 promotes LPS-induced M1 polarization and apoptosis in microglia by mediating the expression of immune and inflammation-related genes.

CXCR2 mediates rotenone-induced neuroinflammation and neurodegeneration through neurotrophil infiltration and extracellular traps formation in mice.

The targeting of AKR1C1 synergizes with gefitinib via the STAT3 signaling pathway in EGFR-mutated NSCLC.

IL-11-mediated macrophage crosstalk drives renal inflammation and fibrosis: A novel therapeutic target in chronic kidney disease.

Potential saviour of pulmonary fibrosis: multi-pathway treatment of natural products.

ATB0,+-targeted nanoparticles trigger STAT3-ferroptosis regulatory axis for enhanced gastric cancer therapy.

Therapeutic targeting of ITGA1 delayed retinoblastoma progression through suppression of STAT3 signaling.