Comorbidity risk characteristics of rheumatoid arthritis in the context of depression-associated lipid metabolism.

BACKGROUND: Rheumatoid arthritis (RA) and major depressive disorder (MDD) exhibit significant comorbidity, with shared pathological mechanisms such as inflammation and abnormal lipid metabolism. However, the specific molecular features and functional pathways linking the two diseases remain unclear.

METHODS: This study integrated public transcriptomic data from five MDD and five RA cohorts. Lipid metabolism-related module genes were screened in MDD cohorts and intersected with RA-upregulated differentially expressed genes to construct a candidate set. LASSO regression and machine learning (XGBoost, Random Forest) were used for feature selection and model construction. Functional exploration included protein-protein interaction network analysis, immune infiltration analysis, and multi-cohort validation. To experimentally test the proposed lipid-immune link and a potential neuron-to-synovium axis, we established an in vitro model. Hippocampal HT-22 neurons were subjected to combined glucocorticoid and saturated fatty acid stimulation to mimic MDD-associated stress-lipotoxicity. The conditioned medium (CM) from these neurons was then applied to human fibroblast-like synoviocytes (FLS). The inflammatory and functional responses of FLS were assessed through qPCR, ELISA, and Western blot.

RESULTS: A nine-gene lipid-immune signature (ANXA3, IL18, CD59, TNFSF13B, BMX, WASF1, SLC8A1, COMMD8, NXT2) was identified. It showed excellent discriminative performance in independent RA cohorts (AUC 0.86-1.00) but weaker performance in MDD cohorts (AUC 0.55-0.65). TNFSF13B, IL18, and CD59 were consistently identified as core hubs. The signature's expression correlated significantly with immune cell infiltration in RA. Critically, our in vitro validation demonstrated that CM from lipid-stressed neurons directly activated FLS. This was evidenced by: (i) significant upregulation of CD59 mRNA and protein levels (via qPCR and Western blot); (ii) elevated secretion of key inflammatory mediators IL-6 and MMP3 (via ELISA); and (iii) enhanced migratory capacity of FLS. These data support a putative paracrine communication axis from stressed neurons to synovial cells, suggesting a role for lipid-mediated inflammatory reprogramming.

CONCLUSION: This study identifies a conserved lipid-immune gene signature associated with the risk of MDD-RA comorbidity and provides multi-level validation encompassing bioinformatic prediction, clinical cohort correlation, and direct experimental evidence (qPCR, ELISA, WB). The signature may represent an immune-inflammatory state activated in a subset of MDD individuals that overlaps with RA pathology. Based on the hub genes, a "Lipid Metabolism - Membrane Microenvironment - Immune Inflammation" axis hypothesis is proposed. The experimentally demonstrated neuron-synovium paracrine axis, characterized by specific molecular changes (CD59, IL-6, MMP3), offers a novel and testable mechanistic conduit for cross-disease pathology, providing new molecular insights and directions for understanding psychiatric-immune comorbidity.