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PubMed2026

FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy.

Autoantibody- and complement-mediated cytotoxicity can cause autoimmune astrocytopathy that leads to CNS inflammatory demyelination. Formyl peptide receptor 2 (FPR2/ALX) governs the activation and propagation of immune response. However, the precise role of FPR2/ALX in neuroinflammation and the effect of FPR2/ALX stimulation on autoimmune astrocytopathy are poorly understood. Using a mouse model of autoimmune astrocytopathy induced by AQP4-IgG- and complement-mediated cytotoxicity, we found that the stimulation of FPR2/ALX with the small-molecule agonist Quin-C1 led to reduced brain lesion volume, astrocyte loss and demyelination. This was accompanied by enhanced anti-inflammatory activity of microglia and reduced infiltration of lymphocytes in the brain. FPR2/ALX stimulation also led to increased phosphorylation of SYK and AKT in mice with autoimmune astrocytopathy. Notably, the benefits of FPR2/ALX stimulation were attenuated in mice with autoimmune astrocytopathy after microglial depletion using the CSF1R inhibitor PLX5622 or natural killer (NK) cell depletion using an anti-NK1.1 monoclonal antibody. Additionally, the protective effects of FPR2/ALX stimulation were diminished in mice with autoimmune astrocytopathy that received the SYK inhibitor R406. Collectively, our findings demonstrate that FPR2/ALX stimulation may represent a promising therapeutic strategy to attenuate detrimental neuroinflammation in autoimmune astrocytopathy by modulating microglia and NK cells. FPR2/ALX stimulation suppresses autoimmune astrocytopathy: Using a mouse model of autoimmune astrocytopathy, we demonstrated that FPR2/ALX stimulation with the small molecule Quin-C1 reduces the CNS infiltration of lymphocytes and augments the anti-inflammatory activity of microglia, leading to attenuated astrocyte pathology induced by AQP4-IgG and complement-mediated attacks. Mechanistically, the benefits of FPR2/ALX stimulation using Quin-C1 involve microglia, natural killer (NK) cells, and SYK-AKT signaling.

Animals↗

PubMed2015

Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.

B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

Amino Acid Motifs↗

PubMed2026

Multi-omics identification of therapeutic targets of compound sappan decoction in hepatocellular carcinoma.

BACKGROUND: Compound sappan decoction (CSD) is a multi-herbal traditional Chinese medicine formulation with clinical relevance in hepatocellular carcinoma (HCC). However, its therapeutic mechanisms remain unclear. METHODS: Bioactive compounds of CSD were identified and standardized using pharmacological and chemical databases. Potential targets were predicted via multiple target inference platforms. HCC-related genes were curated from comprehensive disease databases. Summary-data-based Mendelian randomization (SMR) was conducted to infer causal relationships between compound targets and HCC risk using large-scale quantitative trait loci (QTL) datasets and HCC genome-wide association study data. Colocalization analysis, protein-protein interaction (PPI) network construction, and GO/KEGG enrichment were performed on SMR-identified targets. Molecular docking evaluated binding affinities of representative compounds to prioritized targets. RESULTS: A total of 784 overlapping genes between predicted CSD targets and HCC-related genes were subjected to SMR analysis. Among these, 22 targets were significantly associated with HCC risk based on transcriptomic or proteomic QTLs and showed colocalization evidence. Notably, four targets (ADRB2, APOE, SYK, and PGF) were supported by both replication in an independent cohort and strong colocalization. These 22 targets were enriched in apoptosis, PI3K-Akt signaling, redox metabolism, and detoxification pathways. PPI analysis revealed central hubs including MMP9, BCL2, CASP1, and MCL1. Molecular docking demonstrated strong binding of APOE to quercetin, PGF to luteolin-7-olate, and SYK to kaempferol. CONCLUSIONS: CSD may exert therapeutic effects on HCC through modulation of genetically validated targets involved in tumor progression, inflammation, and metabolic reprogramming, supporting its potential clinical utility as an adjunctive treatment strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12672-026-04740-8.

Caesalpinia↗

PubMed2025

Comprehensive Analysis of Clinical and Molecular Features in Cancer Patients Associated With Major Human Oncoviruses.

Viral infections contribute to a higher incidence of cancer than any other individual risk factor. This study aimed to compare the clinical and molecular features of four viral-associated cancers: stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and cervical squamous cell carcinoma (CESC). Patients were categorized based on viral infection status, as provided in the clinical data, into virus-associated and non-virus-associated groups, followed by a comprehensive comparison of clinical and molecular features. Our analysis disclosed that viral infections confer unique clinical and molecular signatures to their associated tumors. Specifically, human papillomavirus-associated (HPV+) HNSC and hepatitis B virus-associated (HBV+) LIHC patients were predominantly male, younger, and exhibited better clinical prognoses. Virus-associated tumors displayed enhanced immune microenvironments and high DNA damage response scores, while non-virus-associated tumors were enriched in stromal signatures. HPV+ HNSC and Epstein-Barr virus-associated (EBV+) STAD showed similarities across multi-omics features, including better responses to immunotherapy, lower TP53 mutation rates, tumor mutation burden (TMB), and copy number alteration (CNA). Conversely, HBV+, Hepatitis C virus-associated (HCV+) LIHCs and HPV+ CESC were more genomically unstable due to high TP53 mutation rates, TMB, and CNA. At the protein level, Caspase-7 and Syk were upregulated in HPV+ HNSC and EBV+ STAD, and positively correlated with the enrichment levels of CD8 + T cell, PD-L1, and cytolytic activity. Patient stratification based on infection status has significant clinical implications, particularly for patient prognosis and drug response.

Humans↗

PubMed2026

Genetic evidence supports the prioritization of CD40 among prespecified immune-related candidate drug targets in myasthenia gravis.

AIM: To prioritize prespecified immune-related candidate drug targets in myasthenia gravis for further validation based on integrated genetic evidence. METHODS: We integrated drug-target Mendelian randomization (MR) using cis-expression quantitative trait loci (cis-eQTLs), protein-level MR of plasma CD40 abundance using plasma protein quantitative trait loci (pQTLs), and colocalization analyses to evaluate genetically proxied associations with overall MG, early-onset myasthenia gravis (EOMG), and late-onset myasthenia gravis (LOMG). RESULTS: In this study, CD40 showed the most consistent genetic evidence among the six prespecified targets. Effect estimates are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Higher CD40 expression proxied by cis-eQTLs was associated with increased risk of overall MG (OR = 1.14, 95% CI: 1.05-1.24, Bonferroni-adjusted p = 0.022) and EOMG (OR = 1.32, 95% CI: 1.12-1.56, Bonferroni-adjusted p = 0.015). Genetically predicted higher plasma CD40 protein abundance was associated with increased overall MG risk (OR = 1.31, 95% CI: 1.08-1.57, Bonferroni-adjusted p = 0.010), whereas the protein-level MR result for EOMG was directionally consistent but not statistically significant. Colocalization analysis provided suggestive but not definitive evidence of colocalization between CD40 expression and EOMG risk. FCGRT, IL2RA, and SYK showed additional exploratory MR signals requiring further validation. CONCLUSION: CD40 showed the most consistent genetic support among the prespecified targets, supporting its prioritization for functional validation and further therapeutic investigation in MG.

CD40↗

PubMed2025

The mhqPOD gene cluster in lignin-degrading Paenibacillus sp. B2 encodes a pathway for the degradation of lignin-derived 5,5'-di(dehydrovanillic acid) (DDVA).

Lignin-degrading bacteria Paenibacillus sp. B2, Agrobacterium sp. B1, and Ochrobactrum sp. each contain mhqO genes encoding ring cleavage dioxygenase enzymes whose biochemical function is unknown. Each of these strains was found to degrade the biphenyl-containing lignin fragment 5,5'-di(dehydrovanillic acid) (DDVA) on solid media. An operon of five mhq genes in Paenibacillus sp. B2 was analysed via gene expression using quantitative PCR, and all five genes were highly induced (400-1000-fold overexpression) by the presence of DDVA. Recombinant azoreductase MhqP was found to demethylate DDVA to its monodemethylated derivative. Hence, these genes are proposed to be responsible for DDVA degradation, via a pathway involving the same biochemical steps as that studied in Sphingobium lignivorans SYK-6, but using several unrelated genes. Decarboxylation of later pathway intermediate 5-carboxyvanillic acid in Paenibacillus sp. B2 is proposed to be catalysed by decarboxylase UbiD, whose gene is also upregulated in the presence of DDVA. Degradation of the other fragment 4-carboxy-2-hydroxypentadienoic acid is proposed to occur via hydratase UxuA, whose gene is also upregulated by DDVA, and 4-hydroxy-4-methyl-2-oxoglutarate aldolase.

Paenibacillus↗

PubMed2026

Gut microbiota dysbiosis and host metabolite-immune crosstalk drives the pathogenesis of neonatal lupus erythematosus: a multi-omics analysis.

BACKGROUND: Neonatal lupus erythematosus (NLE) is a rare autoimmune condition triggered by the transplacental transfer of maternal antibodies. Despite its recognized clinical manifestations, the underlying pathogenesis remains incompletely understood. This study seeks to explore the disruption of the gut microbiota-host metabolism-immune axis in anti-Ro/La-positive neonates, and to assess its potential role in the development of NLE. METHODS: This multicenter, cross-sectional study included 90 neonates, divided into three groups: 30 with neonatal lupus erythematosus (NLE), 30 with positive antibodies but without clinical manifestations (No-NLE), and 30 healthy controls. We performed 16 S rRNA sequencing to analyze gut microbiota composition, untargeted plasma metabolomic profiling, and proteomic analysis to identify alterations associated with the pathogenesis of NLE. RESULTS: We identified significant alterations in the gut microbiota, plasma metabolome, and proteome profiles of anti-Ro/La-positive neonates. NLE infants exhibited marked enrichment of Enterobacteriaceae and depletion of Bifidobacterium and Clostridium butyricum. Metabolomic analysis revealed hyperactivation of β-alanine and purine metabolism, along with impaired α-linolenic acid metabolism and endocannabinoid signaling. Proteomic profiling indicated aberrant protein expression that modulated IFN signaling, particularly within the C-type lectin receptor pathway. Dysregulation of the spleen tyrosine kinase (SYK) and high-affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) decoupling was observed, correlating with elevated IFN-α and NF-κB p65 levels. Integrated correlation analysis revealed significant associations among differential microbial taxa, plasma metabolites, and proteins. Notably, E. coli-associated metabolites and proteins displayed inverse relationships with those associated with C. butyricum. CONCLUSIONS: These findings represent comprehensive evidence of dysregulation along the "gut microbiota-host metabolism-immune" axis in neonatal lupus erythematosus (NLE), providing novel insights into the disease's underlying heterogeneity.

Humans↗

PubMed2025

Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis.

Yersinia pestis is the bacterium responsible for plague, one of the deadliest diseases in history. To discover human genetic determinants of Y. pestis infection, we utilized nearly 1,000 genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study. A nonsynonymous SNP, rs2282284 (N721S), in Fc receptor-like 3 (FCRL3) was associated with bacterial invasion of host cells (p = 9 × 10-8). Overexpressed FCRL3 facilitated attachment and invasion of Y. pestis and colocalized with Y. pestis at attachment sites. These properties were variably conserved across the FCRL family, revealing an immunoglobulin-like domain and signaling motifs shared by FCRL3 and FCRL5 to be necessary for attachment and invasion. Direct binding to FCRL5 extracellular domain was confirmed, and B cells (the primary cells that express FCRLs) were preferentially invaded by Y. pestis. Thus, Y. pestis hijacks FCRL proteins, possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.

Yersinia pestis↗