This study identified 13 endoplasmic reticulum stress (ERS)-related biomarkers associated with multiple sclerosis (MS) through integrated bioinformatics analysis (including weighted gene co-expression network analysis and machine learning algorithms) and single-cell sequencing, combined with validation in an experimental autoimmune encephalomyelitis (EAE) mouse model. Among them, GPX1, RCN1, and UBE2D3 exhibited high diagnostic value (AUC > 0.7, p < 0.05), and the diagnostic potential of GPX1 and RCN1 was confirmed in the animal model. The study found that memory B cells, plasma cells, neutrophils, and M1 macrophages were significantly increased in MS patients, while naive B cells and activated NK cells decreased. Consensus clustering based on key ERS-related genes divided MS patients into two subtypes. Single-cell sequencing showed that microglia and pericytes were the cell types with the highest expression of key ERS-related genes, and the APP-CD74 pathway was enhanced in the brain tissue of MS patients. Mendelian randomization analysis suggested that GPX1 plays a protective role in MS. These findings reveal the mechanisms of ERS-related biomarkers in MS and provide potential targets for diagnosis and treatment.

Breast cancer (BC) heterogeneity necessitates prognostic and therapeutic biomarkers. PANoptosis remains incompletely understood with regard to its role in BC immunomodulation and clinical outcomes. Here, we integrated transcriptomic data from 7067 patients with BC across multiple cohorts. Patients were stratified via non-negative matrix factorization based on PANoptosis-related gene expression, revealing three distinct clusters. Cluster C3 exhibited the poorest overall survival, characterized by upregulated lipid metabolism and suppressed immunity. A prognostic signature was constructed using a random survival forest model and served as an independent prognostic factor. Single-cell RNA sequencing of 31 tumors identified IL-33-expressing endothelial subclusters (ACKR1⁺ and FBLN5⁺) as key regulators of the tumor immune microenvironment. Reduced IL-33 expression correlated with increased M2 macrophages and CD4⁺ T cell depletion, while sex-specific analysis revealed IL-33 as a predictor of immunotherapy response. Our findings underscore the role of PANoptosis and IL-33⁺ endothelial cells in shaping BC immunity and prognosis.