Ruyu Bai

Alzheimer’s disease (AD) has a complex pathogenesis, involving molecular and neuroimmune dysregulation, but the causal drivers linking transcriptomic changes to immune remodeling are not yet clear. In a discovery cohort, differential expression analysis was performed, and it was independently validated in two external cohorts. Key genes were prioritized via LASSO/logistic regression, functionally annotated, and causally linked to AD using two-sample MR. The neuroimmune landscape was mapped by ssGSEA, and top candidates were validated in vitro. RGS1 is a key node in neuroinflammation and cytoskeletal dynamics, which is prioritized by the algorithmic intersection. MR analysis suggested a potential causal association between genetically predicted RGS1 expression and AD risk. RGS1 was consistently upregulated in both discovery and validation cohorts (AUC: 0.61–0.67) and was confirmed in vitro. Immune deconvolution showed that AD-specific enrichment profiles occur, and RGS1 is strongly correlated with activated CD4+ T cells and pro-inflammatory chemokines. RGS1 is identified as a robust key gene that may contribute to immune microenvironment dysregulation in AD, and combining discovery-validation transcriptomics, causal inference, and experimental validation, we find that RGS1 is a potential immunomodulatory target.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality, underscoring the need for new molecular markers to enable early detection and clarify underlying mechanisms. Iron metabolism is linked to oxidative stress, endothelial injury, and inflammation, all central to thrombosis, yet its transcriptomic contribution to VTE remains unclear. We analyzed gene expression profiles from GSE19151 and GSE48000 using differential expression and weighted gene co-expression network analysis (WGCNA), integrating results with an iron metabolism gene set. Three hub genes were identified, arachidonate 5-lipoxygenase (ALOX5), Rho GTPase activating protein 1 (ARHGAP1), and glucose-6-phosphate dehydrogenase (G6PD), all downregulated in VTE. Gene set enrichment indicated that ALOX5 is involved in endothelial regulation, lipid metabolism, and immune pathways. A three-gene signature showed high diagnostic accuracy (AUC = 0.924 in the discovery cohort; 0.705 in validation). Immune deconvolution revealed broad immune remodeling and associated ALOX5 with multiple immune cell subsets, especially M0 macrophages, and with regulators such as TGFB1 and IL6R. Western blot analysis further showed that ALOX5 protein expression was significantly increased in LPS-activated HUVECs, supporting its involvement in inflammatory endothelial injury. DrugBank screening identified 19 approved drugs targeting ALOX5, supporting its potential for mechanistic and clinical investigation.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with unclear pathogenic mechanisms. Dysregulated zinc metabolism contributes to AD pathology. This study aimed to identify zinc metabolism-related hub genes to provide potential biomarkers and therapeutic targets for AD. Methods: We performed an integrative analysis of multiple transcriptomic datasets from AD patients and normal controls. Differentially expressed genes and weighted gene co-expression network analysis (WGCNA) were combined to identify hub genes. We then conducted Gene Set Enrichment Analysis (GSEA), immune cell infiltration analysis (CIBERSORT), and receiver operating characteristic (ROC) curve analysis to assess the hub gene’s biological function, immune context, and diagnostic performance. Drug-gene interactions were predicted using the DrugBank database. Results: We identified a single key zinc transporter–related hub gene, SLC30A3, which was significantly downregulated in AD and demonstrated potential diagnostic value (AUC 0.70–0.80). Lower SLC30A3 expression was strongly associated with impaired synaptic plasticity (long-term potentiation, long-term depression, calcium signaling pathway, and axon guidance), mitochondrial dysfunction (the citrate cycle and oxidative phosphorylation), and pathways common to major neurodegenerative diseases (Parkinson’s disease, AD, Huntington’s disease, and amyotrophic lateral sclerosis). Furthermore, SLC30A3 expression correlated with specific immune infiltrates, particularly the microglia-related chemokine CX3CL1. Zinc chloride and zinc sulfate were identified as potential pharmacological modulators. Conclusions: Our study systematically identifies SLC30A3 as a novel biomarker in AD, linking zinc dyshomeostasis to synaptic failure, metabolic impairment, and neuroimmune dysregulation. These findings offer a new basis for developing targeted diagnostic and therapeutic strategies for AD.