Folic Acid Targeting Shared Sepsis-Osteoporosis Pathogenesis: From Computational Discovery to Dynamic Binding Mechanisms.

Abstract

Sepsis and osteoporosis (OP) are two common diseases that have a significant impact on public health. This study aims to elucidate the common genetic factors and molecular mechanisms underlying the relationship between sepsis and osteoporosis and to explore novel treatment methods. We employed a comprehensive bioinformatics approach, utilizing gene expression data from multiple human databases. This approach included differential expression analysis, weighted gene coexpression network analysis (WGCNA), enrichment analysis, machine learning, immune infiltration analysis, and molecular docking and molecular dynamics simulations. Our study identified four key genes, CTSD, RNASE2, KYNU, and CX3CR1, that are associated with both sepsis and OP. Functional enrichment analysis revealed significant connections to immune processes and signaling pathways, including autophagy and the IL-17 signaling pathway. A nomogram constructed from these four genes demonstrated a strong diagnostic performance for OP, achieving an area under the curve (AUC) of 0.797 (95%CI: 0.712-0.882). Additionally, the validation data set for sepsis demonstrated an even higher AUC of 0.903 (95%CI: 0.825-0.980). Moreover, the immune infiltration analysis revealed significant correlations between these key genes and various immune cell types, suggesting that modulating the immune cell activity could be a potential therapeutic target. Furthermore, molecular docking studies identified folic acid as a promising therapeutic candidate for both sepsis and OP due to its strong binding affinity with the protein products of the four key genes. Molecular dynamics simulations further confirmed the stability of these binding interactions. This research offers important insights into the common genetic framework linking sepsis and osteoporosis. It integrates bioinformatics and molecular simulations to decipher the protective role of folic acid in sepsis and osteoporosis.