Virtual single‐cell perturbation and genetic causal inference reveal CSF1R ‐dependent immunometabolic communication in iron metabolism‐associated osteoarthritis
Integrative genetic and single-cell analysis reveals CSF1R-driven macrophage remodeling in iron-associated osteoarthritis, highlighting a therapeutic target for degenerative joint disease.
Key Points
To identify the causal genetic mechanisms and immune cell communication pathways connecting iron dysregulation to joint degeneration in osteoarthritis.
Screened iron-metabolism genes, differential expression profiles, and eQTL data, prioritizing candidates using machine learning and Mendelian randomization.
Conducted single-cell transcriptomics, mediation analysis spanning 731 immune cell traits and 1,400 metabolites, and in silico virtual gene perturbations.
Performed molecular docking, molecular dynamics simulations, and in vitro validation of CSF1R expression in inflamed macrophages.
Identified CSF1R as a central causal regulatory gene predominantly expressed in joint macrophages and colocalizing with osteoarthritis susceptibility.
Discovered through mediation analysis that CD14+CD16+ monocytes, rather than circulating metabolites, mediate the pathway linking CSF1R activity to disease risk.
Demonstrated via virtual perturbation that CSF1R knockdown enhances antigen processing and phagosomal programs, whereas CSF1R overexpression stimulates cartilage-degrading and extracellular matrix remodeling pathways.