The newly discovered Treg subset (CLA+ Tregs) expressing cutaneous lymphocyte-associated antigen is associated with inflammatory conditions. This study elucidated the role of CLA+ Tregs in rheumatoid arthritis (RA) development and its responses to treatment. A total of 12 T cell subsets, together with total T cells, B cells, and NK cells were analyzed in 169 patients with RA and 114 healthy controls using flow cytometry. Autoantibodies were detected by ELISA. The logistic regression models were employed to assess the association between cell subsets and rheumatoid arthritis. Relationships between CLA+ Tregs and clinical variables were assessed. Among the immune cell subsets analyzed, CLA⁺ Tregs were the most significantly reduced ones in patients with RA compared with healthy controls (OR 0.825 [0.764–0.891], p < 0.001). Decreased CLA⁺ Tregs were strongly correlated to active disease status (adjusted OR 0.814 [0.733–0.902], p = 0.004; AUC 0.916 [0.869–0.963], p < 0.001). Decreased CLA+ Tregs were associated with higher swollen joint count, tender joint count and DAS28 scores, as well as systemic involvements, including interstitial lung disease (ILD), anemia, fever, and skin vasculitis. Additionally, rheumatoid factor (RF) and anti-mutated citrullinated vimentin antibody (anti-MCV) were correlated to lower CLA+ Tregs. Compared to baseline prior treatment, CLA+ Tregs increased significantly in RA patients, accompanied by improvements in disease activity (median, 9.60

Objective: The causal effect between major depressive disorder (MDD) and asthma-related situations (asthma phenotypes and asthma outcomes) was rarely evaluated. The objective of our study was to not only assess the potential causal links of MDD on asthma phenotypes and asthma-related outcomes, but the mediating effect of FEV1 (forced expiratory volume in the first second) on asthma phenotypes and asthma-related outcomes caused by MDD. Method: By operating the Two-Sample and Bayesian Weighted mendelian randomization (MR) analysis, we explored the potential causal effect of MDD and FEV1 on asthma phenotypes (childhood asthma, adult asthma, obesity asthma, allergic asthma and non-allergic asthma) and asthma-related outcomes (asthma-related hospital admissions, asthma exacerbations, asthma with acute respiratory infections and asthma with pneumonia) from genome-wide association studies (GWAS) database. Furthermore, genetic correlation was also evaluated by the analysis of linkage disequilibrium score regression (LDSC). Results: The LDSC and MR analysis demonstrated that MDD had an increased risk on FEV1, adult asthma, obesity asthma, allergic asthma, non-allergic asthma, asthma-hospital admissions, asthma exacerbations, asthma with acute respiratory infections, asthma with pneumonia. FEV1 indicated mediated effect of MDD on adult asthma, obesity asthma, allergic asthma, non-allergic asthma, asthma-related hospital admissions, asthma with acute respiratory infections and asthma with pneumonia. Conclusion: Our investigation showed that MDD had significant genetic correlations and causal relationships with FEV1, a majority of asthma phenotypes and outcomes. FEV1 indicated mediated effect of MDD on asthma phenotypes and outcomes, which may benefit clinical practice in the treatment of asthma phenotypes and poor prognosis.

Background:Thimerosal is a mercury-containing preservative widely used in vaccines. This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies, particularly colorectal cancer (CRC) and melanoma. Methods:A combination of in vitro and in vivo approaches was employed. Cell proliferation, apoptosis, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), colony formation, ATP viability, Western blotting, flow cytometry, wound-healing and Transwell assays. Subcutaneous, lung metastases, and Azoxymethane/Dextran Sulfate Sodium Salt (AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety. The functional role of mercury ions was validated using structural analogues. Mechanistic studies included RNA sequencing, Western blot, and immunohistochemical analysis of CD8+ T cell infiltration. The synergistic effect with programmed cell death protein 1 (PD-1) antibody therapy was also evaluated. Results:Thimerosal potently inhibited tumor growth (with IC50 values ranging from 0.1 to 1 μM in vitro) and significantly prolonged survival without overt toxicity in vivo. Mechanistically, mercury ions were identified as critical functional sites mediating Thimerosal's antitumor effects. Specifically, Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1) and signal transducer and activator of transcription 3 (STAT3). Furthermore, it enhanced the infiltration of CD8+ T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy. Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8+ T cell recruitment. It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.

Background As a non-invasive therapy in traditional Chinese medicine (TCM), Tuina maintains systemic homeostasis by stimulating acupoints, unblocking meridians, and regulating yin-yang balance. Objective This study was performed to explore the effects of Tuina on oxidative stress dysregulation in SAMP8 mice, and to clarify whether Tuina can serve as a non-pharmacological intervention to ameliorate age-related mild cognitive impairment (MCI) and retard cognitive decline. Methods Six-month-old SAMP8 mice were selected as aging models, and age-matched SAMR1 mice served as normal controls. Four groups were set: Control, Model, Tuina, and Tuina+SIRT3 inhibitor (3-TYP). Learning and memory were tested via the Morris water maze (MWM) and novel object recognition (NOR). Hippocampal pathology, neuronal apoptosis, and mitochondrial function were observed by immunohistochemistry, histochemistry, and transmission electron microscopy. Mitochondrial reactive oxygen species (ROS), respiratory chain complex activities, relative mtDNA content, and the protein expressions of PGC-1α, SIRT3, and p-FOXO3a were quantitatively analyzed. Results Tuina treatment significantly shortened the escape latency in the MWM (P < 0.01) and increased the discrimination index in the NOR test (P < 0.01) compared with the Model group. Biochemically, Tuina markedly reduced hippocampal ROS levels and MDA content (P < 0.01), while elevating the activities of antioxidant enzymes, including SOD and CAT (P < 0.01). Furthermore, Tuina restored mitochondrial respiratory chain complex activities and relative mtDNA content, and significantly upregulated the protein levels of PGC-1α, SIRT3, and p-FOXO3a (P < 0.01). Notably, these beneficial effects were largely abrogated by the administration of the SIRT3 inhibitor 3-TYP. Conclusion Tuina exerts neuroprotective effects by activating the PGC-1α/SIRT3/FOXO3a pathway. This mechanism improves mitochondrial function, sustains ROS homeostasis, alleviates oxidative stress injury, and ameliorates hippocampal lesions, thereby delaying brain aging and cognitive decline.

Background:Colorectal cancer (CRC) patients are more susceptible to infections due to immune dysregulation. The interleukin-17A (IL-17A) signaling pathway plays a critical role in both immune defense and cancer metastasis. This study aimed to identify novel microRNAs (miRNAs) involved in IL-17A-mediated CRC progression. Methods:RNA sequencing (RNA-seq) was used to analyze gene expression in stimulated peripheral blood mononuclear cells (PBMCs) and HCT116 cells cultured with their conditioned media (CM). Candidate miRNAs involved in IL-17A or transforming growth factor-β (TGF-β)-driven CRC progression were evaluated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), western blotting, and wound healing assays. Prognostic relevance was assessed in The Cancer Genome Atlas colon adenocarcinoma (TCGA-COAD) cohort via Cox regression and Kaplan-Meier survival analysis. Results:IL-17 signaling emerged as one of the most significantly enriched pathways following immune stimulation. Both IL-17A and TGF-β upregulated the epithelial-mesenchymal transition (EMT) marker vimentin and promoted CRC cell migration. Among the five candidate miRNAs identified, miR-501-5p was markedly induced by IL-17A and TGF-β. Functional assays revealed that either transient overexpression or inhibition of miR-501-5p significantly altered CRC cell migration in response to IL-17A. Notably, elevated miR-501 expression was associated with more than a twofold increased risk of death in stage IV CRC patients from the TCGA-COAD cohort. Conclusions:IL-17 signaling may drive CRC progression and poor clinical outcomes in part through the induction of miR-501-5p, underscoring its potential role in immune-related cancer metastasis and as a prognostic biomarker.

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.

Subnuclear compartmentalization has emerged as a critical determinant of transcriptional homeostasis and cell-fate determination. The nucleolus scaffolds specialized heterochromatin, yet the mechanisms orchestrating its spatial assembly and therapeutic relevance remain elusive. Here we identify the nucleolar deubiquitinase OTUD4 as a key coordinator of heterochromatin architecture. We demonstrate that casein kinase II (CK2)-mediated phosphorylation serves as a molecular switch to activate OTUD4, which functions as a phospho-activated, K63-specific deubiquitinase. Crucially, we show that the spatial anchoring of H3K9me3-marked heterochromatin to the nucleolar surface is molecularly mandated by the K63-linked ubiquitination status of Nucleophosmin (NPM1) at the Lys27 (K27) residue. OTUD4-mediated deubiquitination of NPM1 K27 is indispensable for stabilizing the NPM1 pentameric scaffold, which in turn sequesters H3K9me3-marked domains at the nucleolar periphery. Disruption of the CK2–OTUD4–NPM1 axis triggers heterochromatin detachment, eliciting nucleolar stress and retroelement derepression. This epigenetic collapse activates cytosolic DNA-sensing pathways to potentiate tumor-intrinsic immunogenicity. Clinically, an OTUD4-nucleolus gene signature correlates with adverse survival and immunotherapy resistance. Together, these findings establish a phosphorylation–deubiquitination cascade to preserve heterochromatin topology and nominate spatial epigenetic targeting as a translational strategy to overcome immune evasion in refractory malignancies.

In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.

BackgroundFusobacterium nucleatum (Fn), a gram-negative oral bacterium, has been implicated in promoting colorectal cancer (CRC) progression by modulating the inflammatory microenvironment. Recent studies have shown that gut microbiota imbalance plays a crucial role in CRC development, and Fn, specifically, has been found to exist in the intestine and exert pro-tumorigenic effects. However, the precise mechanisms underlying Fn-induced CRC progression remain elusive.MethodsA systematic experimental strategy was adopted to explore the function of Fusobacterium nucleatum (Fn) in colorectal cancer (CRC) progression. Tissue specimens were collected from healthy volunteers, patients with ulcerative colitis (UC), colorectal adenoma (CRA) and CRC at the First Affiliated Hospital of Henan University of Science and Technology via colonoscopy and surgical resection. Two CRC mouse models, subcutaneous MC38 model and AOM-DSS orthotopic model, were constructed, followed by intratumoral injection or oral gavage of Fn, Streptococcus mutans (S.M.) or normal saline. qPCR was used to quantify Fn abundance in colorectal tissues. IHC and FISH detected inflammatory cytokines and immune cells in tumor tissues. 16S rRNA amplicon sequencing analyzed Fn-mediated alterations in mouse gut microbiota. Flow cytometry and ELISA evaluated immune cell subsets and inflammatory cytokine levels. Western blot examined NLRP3 inflammasome and other proteins expression.ResultsIn this study, we employed two mouse models of CRC (MC38 subcutaneous and AOM-DSS orthotopic models) to investigate the role of Fn in CRC progression. Our findings demonstrated that Fn administration significantly increased tumor growth compared to controls. Quantitative PCR confirmed elevated Fn abundance in CRC tissues, and microbiome analysis revealed distinct bacterial clades in Fn-treated mice. Immunofluorescence analysis showed enrichment of myeloid cells (CD45/CD11b, CD11C, F4/80,MHCI,MHCII) in tumors, suggesting that Fn reshapes the immune landscape towards a proinflammatory state. In vitro and in vivo experiments further revealed that Fn selectively expands myeloid-derived immune cells. Critically, Fn failed to induce tumor growth in NLRP3-/- mice, confirming that NLRP3 inflammasome activation is a key mechanism in Fn-induced CRC progression.ConclusionOur results establish Fn as a driver of CRC progression through bone marrow-derived immune cell recruitment and NLRP3-dependent inflammatory microenvironment induction. These findings provide new insights into the mechanisms by which Fn contributes to CRC development and suggest potential therapeutic targets for CRC prevention and treatment.

Amino acids are organic compounds that serve as the building blocks of proteins and peptides. Additionally, they function as bioactive molecules that play important roles in metabolic regulation and signal transduction. The ability of cells to sense fluctuations in intracellular and extracellular amino acid levels is vital for effectively regulating protein synthesis and catabolism, maintaining homeostasis, adapting to diverse nutritional environments and influencing cell fate decision. In this review, the recent molecular insights into amino acids sensing are discussed, along with the different sensing mechanisms in distinct organisms.

Despite wide variation, each cell type has an optimal size. Maintaining optimal size is essential for cellular fitness and function but the biological basis for this remains elusive. Here, we performed fitness analysis involving genome-wide CRISPR-Cas9 knockout data from tens of human cell lines and identified that cell size influences the essentiality of genes related to mitochondria and membrane repair. These genes also included glutathione peroxidase 4 (GPX4), which safeguards membranes from oxidative damage and prevents ferroptosis-iron-dependent death. Growth beyond normal size, with or without cell-cycle arrest, increased lipid peroxidation, resulting in a ferroptosis-sensitive state. Proteomic analysis revealed cell-cycle-independent superscaling of endoplasmic reticulum, accumulation of iron, and lipidome remodeling. Even slight increases from normal cell size sensitized proliferating cells to ferroptosis as evidenced by deep-learning-based single-cell analysis. Thus, lipid peroxidation may be a fitness trade-off that constrains cell enlargement and contributes to the establishment of an optimal cell size.

The tumor immune microenvironment (TIME) represents a complex battlefield where metabolic competition and immune evasion mechanisms converge to drive cancer progression. Amino acids, with their multifaceted biological roles, have emerged as pivotal regulators of tumor cell proliferation and immune cell functionality. The sensing mechanisms by which amino acids within the tumor microenvironment influence cellular growth, survival, and immune function are systematically explored in this review; the latest advances in understanding amino acid metabolism in tumor biology are also reviewed. In addition, the multifaceted roles of key amino acids in shaping the TIME with particular emphasis on tumor immunity and malignant growth were investigated. Finally, emerging therapeutic strategies targeting amino acid metabolism to reprogram the TIME are discussed, highlighting promising approaches, such as CAR-T cell therapy and engineered bacterial interventions. Through this comprehensive analysis, critical insights into future research directions and potential clinical translation of amino acid-targeted interventions are provided.

BACKGROUND:Lung cancer, particularly lung adenocarcinoma, poses a significant health challenge due to its high incidence and mortality rates. Despite advancements in targeted therapies, treatment outcomes for lung adenocarcinoma remain unsatisfactory. This study explores the role of the histone acetyltransferase MYST2 in lung adenocarcinoma and its potential as a therapeutic target. METHODS:An analysis using the TIMER 2.0 and TCGA databases was performed to compare the expression levels of MYST2 between lung adenocarcinoma tissues and normal tissues. Functional assays, including cell proliferation, migration, and invasion, were conducted to evaluate the effects of MYST2 overexpression and knockout in lung cancer cells. Co-immunoprecipitation and GST pull-down assays were utilized to identify interactions involving the MYST domain of MYST2 and p38, while also assessing the impact of MYST2 on the binding between MEK6 and p38. RESULTS:The analysis revealed that MYST2 was significantly up-regulated in lung adenocarcinoma tissues compared to normal tissues and was associated with poor prognosis. Functional assays demonstrated that MYST2 overexpression promoted, whereas MYST2 knockout inhibited, lung cancer cell proliferation, migration, and invasion. Mechanistically, MYST2 enhanced the phosphorylation of p38 and ERK. Co-immunoprecipitation and GST pull-down assays identified the MYST domain of MYST2 as crucial for its interaction with p38. Additionally, MYST2 overexpression facilitated the binding of MEK6 to p38, indirectly influencing p38 activity. CONCLUSION:These findings suggest that MYST2 acts as an oncogene in lung cancer by modulating p38 phosphorylation through the MYST domain, underscoring its potential as a prognostic marker and therapeutic target.

ObjectiveSystemic lupus erythematosus (SLE) is complexed with multi systemic involvements associated with genetic and environmental factors. Herein, we delve into the molecular mechanism behind COVID-19 vaccine-induced SLE.MethodsTo elucidating the molecular mechanism, we employed the whole genome sequencing (WGS) and immune cell RNA sequencing of CD4+ T, CD8+ T, and B cells.ResultsOur findings suggest that in genetically predisposed individuals, COVID-19 vaccination might provoke SLE by triggering host-harbored virus signaling and cytokine pathway-associated immune response.ConclusionsThis study deepens the underlying mechanism and highlights the importance of evaluating the genetic susceptibility to autoimmune disease before COVID-19 vaccination.

Pancreatic cancer (PC) is frequently referred to as the "king of cancers" due to its high mortality rate and poor prognosis. Chemotherapy drugs of a traditional nature are confronted with a multitude of challenges, including poor water solubility, low bioavailability, significant toxic side effects, and poor patient tolerance. This article provides a comprehensive review of the epidemiological and pathophysiological features of PC. The review also highlights the key antigens and receptors that are overexpressed in PC cells, including antigens such as TROP2, MSLN, MUC, and CA19-9. Furthermore, the article covers receptors like EGFR, TfR, integrins, GPCRs, IGF, GPC1, TF, and MET. The text introduces current pancreatic cancer treatment drugs, including gemcitabine, tegafur, and albumin-bound paclitaxel. The text also discusses targeted drug delivery carriers for PC, including liposomes, carbon nanotubes, exosome, polymer micelles, nanoparticles, nanocrystals, and hydrogel-encapsulated nanoparticles. The review offers a concise overview of the antibodies and ligands employed in active targeted drug delivery systems for PC, including hRS7, αTROP2, MF-T, TAB004, HzMUC1, as well as ligands such as EGF, GE11 peptide, Tf, tTR14, XQ-2d, cNGQ, α5β1-targeted peptide, IGF1, and SDC1. The therapeutic effects and prospects of combining active targeting strategies with photothermal therapy, immunotherapy, and gene editing technology are discussed in this paper.

GO enrichment analysis of genes identified through CUT&Tag data