Multi-Omics Dissection of TIMP1 in Monocytes/Macrophages Reveals Pathogenic Mechanisms and Therapeutic Opportunities in Ankylosing Spondylitis.

The pathogenesis of ankylosing spondylitis (AS) remains unclear, and its treatment poses significant challenges. This study aims to elucidate the underlying mechanisms of AS and explore potential therapeutic targets. We conducted a comprehensive multi-omics analysis, integrating proteomics, miRNA profiling, and single-cell sequencing data. Various analytical methods were employed to investigate the expression, cellular origin, and regulatory mechanisms of the target protein, as well as to explore potential therapeutic strategies. Finally, we established a chronic inflammation model and performed qPCR analysis on the paraspinal ligament muscle. TIMP1, a gene associated with AS, was found to be downregulated in AS. Single-cell sequencing revealed that this reduction was primarily observed in the monocyte/macrophage lineage, especially in CD14+ monocytes. The downregulation of TIMP1 was linked to the overexpression of hsa-miR-8059, hsa-miR-3692-5p, hsa-miR-4481, and decreased STAT1 expression. TIMP1 appears to exert its effects on AS pathogenesis indirectly through RHOA. Therapeutic exploration identified several compounds, including Isotretinoin, Oxaliplatin, Simvastatin, and active components from traditional Chinese medicines (TCM) such as Tripterygii Radix, Niudali, and Cinnamaldehyde, which stably bind to TIMP1. qPCR results showed that TIMP1, STAT1, and RHOA were all significantly downregulated in the paraspinal ligament muscle of the chronic inflammation model. This multi-omics study highlights the role of reduced TIMP1 expression in CD14+ monocytes due to elevated miRNAs and decreased STAT1, contributing to AS pathogenesis via RHOA. The study also identifies several drugs and active compounds with potential therapeutic effects on TIMP1, offering new directions for AS research and treatment.