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Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels ( p  = 0.0006, CI 95%: 4.12, 13.32) and particle number ( p  = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration ( p  = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity ( p  = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele. Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.

Background: The STAT4 gene plays a key role in immune regulation and is associated with susceptibility to autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Objectives: The objective of this study is to analyze variants of uncertain significance (VUSs) in STAT4 using bioinformatics tools to predict their functional and structural impact. Methods: A total of 48,295 variants of the STAT4 gene (ENSG00000138378) were retrieved from the Ensembl database. A tiered filtering approach was used to assess VUS pathogenicity, integrating in silico prediction tools such as SIFT, PolyPhen, MutPred2, and Align-GVGD, as well as structural modeling platforms including Chimera, ModRefiner, Missense3D, HOPE, and DynaMut2. Results: Eighty missense VUSs were identified; of these, 13 were prioritized based on concordant signals across multiple computational predictors. These variants showed significant alterations in the physicochemical properties of the protein, including changes in hydrophobicity and disruption of hydrogen bonding. Notably, the rs140675301 (Glu128Val) variant lies within a conserved loop, and in silico analyses suggest that this mutation may alter kinase specificity regarding the phosphorylation of serine 130. Conclusions: The integrative use of the bioinformatic tools employed represents a valuable preliminary step prior to undertaking more complex and resource-intensive functional studies. This complementary strategy strengthens the interpretative framework for VUS, guiding subsequent experimental validation and supporting a structured assessment of variant relevance, particularly in the context of immune-related genes such as STAT4.

Ovarian cancer (OC) is a high‐mortality gynaecological malignancy, and the role of PANoptosis, a comprehensive cell death mechanism, in its prognosis remains unexplored. This study aims to clarify it, potentially guiding OC diagnosis and treatment. We analysed the ovarian data from TCGA and GTEx, and the GSE184880 scRNA‐seq dataset from GEO. Spatial data and pathological images were sourced from the 10X Genomics website and GDC Portal. Features were extracted using CellProfiler and ResNet‐50, and a PANoptosis‐related pathomics prognostic model (PANPM) powered by deep learning was developed. The PANoptosis‐related hub gene STAT4 potentially served as a protective factor for patients with OC. A better prognosis in OC was found linked to higher PANoptosis. The PANPM, manifesting distinct advantages for clinical application by accurately extracting pathological features, performed excellently in validation and the high‐risk group indicated a poor prognosis. Additionally, STAT4+ T cells may inhibit OC, by activating the PANoptosis of epithelial cells through TNFSF12‐TNFRSF12A and TNF‐TNFRSF1A, which sheds light on potential therapeutic interventions involving STAT4+ T cells.

Intergenic long noncoding RNAs (lincRNAs) regulate gene expression in various tissues. Zhao and colleagues identify 1,524 lincRNA clusters in thymocytes and mature T cell subsets and reveal dynamic and cell-specific patterns of lincRNA expression during T cell differentiation. Although intergenic long noncoding RNAs (lincRNAs) have been linked to gene regulation in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identified 1,524 lincRNA clusters in 42 T cell samples, from early T cell progenitors to terminally differentiated helper T cell subsets. Our analysis revealed highly dynamic and cell-specific expression patterns for lincRNAs during T cell differentiation. These lincRNAs were located in genomic regions enriched for genes that encode proteins with immunoregulatory functions. Many were bound and regulated by the key transcription factors T-bet, GATA-3, STAT4 and STAT6. We found that the lincRNA LincR- Ccr2 -5′AS, together with GATA-3, was an essential component of a regulatory circuit in gene expression specific to the T H 2 subset of helper T cells and was important for the migration of T H 2 cells.

ObjectivesGenetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.ResultsIn resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.ConclusionsT cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.

Bladder cancer (BLCA) is a common genitourinary cancer in patients, and tumour angiogenesis is indispensable for its occurrence and development. However, the indepth mechanism of tumour angiogenesis in BLCA remains elusive. According to recent studies, the tight junction protein family member occludin (OCLN) is expressed at high levels in BLCA tissues and correlates with a poor prognosis. Downregulation of OCLN inhibits tumour angiogenesis in BLCA cells and murine xenografts, whereas OCLN overexpression exerts the opposite effect. Mechanistically, the RT‐qPCR analysis and Western blotting results showed that OCLN increased interleukin‐8 (IL8) and p‐signal transducer and activator of transcription 3 (STAT3) levels to promote BLCA angiogenesis. RNA sequencing analysis and dual‐luciferase reporter assays indicated that OCLN regulated IL8 transcriptional activity via the transcription factor STAT4. In summary, our results provide new perspectives on OCLN, as this protein participates in the development of BLCA angiogenesis by activating the IL8/STAT3 pathway via STAT4 and may serve as a novel and unique therapeutic target.

Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrates that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and ‘memory’ NK cells possess distinct chromatin accessibility states and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. Furthermore, we elucidate how individual STAT transcription factors differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8 + T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8 + T cells. Overall, our study reveals the dynamic nature of epigenetic modifications during the generation of innate and adaptive lymphocyte memory. Natural killer (NK) cells can acquire ‘memory’ signatures. Sun and colleagues examine the dynamic ATAC-seq and functional RNA-seq changes observed upon generation of NK cell memory and show distinct roles for transcription factors STAT1 and STAT4.

ObjectivesTo find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets.MethodsWe performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen).ResultsWe found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10−9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10−160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10−11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63–0.87, p=10−9–10−27) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4.ConclusionSequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.

Our previous study has proved that the Klotho up-regulation participated in cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance. However, the exact neuroprotective mechanism of Klotho in CIP remains unclear. We explored the hypothesis that STAT4-mediated Klotho up-regulation contributes to the CIP-induced brain ischemic tolerance via inhibiting neuronal pyroptosis. Firstly, the expressions of pyroptosis-associated proteins (i.e., NLRP3, GSDMD, pro-caspase-1, and cleaved caspase-1) in hippocampal CA1 region were determined during the process of brain ischemic tolerance. We found the expression of pyroptosis-associated proteins was significantly up-regulated in the ischemic insult (II) group, and showed no significant changes in the CIP group. The expression level of each pyroptosis-associated proteins was lower in the CIP + II group than that in the II group. Inhibition of Klotho expression increased the expression of pyroptosis-associated proteins in the CIP + II group and blocked the CIP-induced brain ischemic tolerance. Injection of Klotho protein decreased the expression of pyroptosis-associated proteins in the II group, and protected neurons from ischemic injury. Secondly, the transcription factor STAT4 of Klotho was identified by bioinformatic analysis. Double luciferase reporter gene assay and chromatin immunoprecipitation assay showed STAT4 can bind to the site between nt − 881 and – 868 on the Klotho promoter region and positively regulates Klotho expression. Moreover, we found CIP significantly enhanced the expression of STAT4. Knockdown STAT4 suppressed Klotho up-regulation after CIP and blocked the CIP-induced brain ischemic tolerance. Collectively, it can be concluded that STAT4-mediated the up-regulation of Klotho contributed to the brain ischemic tolerance induced by CIP via inhibiting pyroptosis.