Molecular insights into the causal role of TG/IDL in rheumatoid arthritis: Integrating Mendelian randomization and single-cell RNA sequencing.

Aims: Triglycerides in intermediate-density lipoproteins (TG/IDL) have been implicated in rheumatoid arthritis (RA) pathogenesis, but their causal relationship and underlying molecular mechanisms remain unclear. This study integrates Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq) to identify key genes mediating the link between TG/IDL and RA.

Materials and methods: GWAS datasets and MR analysis were utilized to establish TG/IDL as a risk factor for RA. scRNA-seq of RA synovial tissue was conducted to examine cellular heterogeneity and identify differentially expressed genes (DEGs). Integration of MR and scRNA-seq data pinpointed key genes, which were validated through functional studies in collagen-induced arthritis (CIA) mouse models and fibroblast-like synoviocyte (FLS) cultures.

Key findings: MR analysis confirmed TG/IDL as a risk factor for RA (OR = 1.001, p = 0.027). scRNA-seq identified seven distinct cell types and highlighted ABCA1, PLTP, and GAS6 as key genes. Overexpression of these genes in CIA mice and FLS cultures reduced inflammation, suppressed cell migration, and inhibited signaling pathways (p65, MAPK, JNK), validating their therapeutic potential.

Significance: This study establishes a molecular link between TG/IDL and RA, identifies novel therapeutic targets, and provides insights into lipid metabolism's role in RA, paving the way for innovative treatment strategies.