This study conducted a proteome-wide Mendelian randomization (MR) analysis to identify therapeutic targets for ankylosing spondylitis (AS), a chronic inflammatory disorder. The researchers utilized plasma protein data from the UK Biobank Pharma Proteomics Project and AS genetic association study data from the Finnish database. They identified six plasma proteins (TNF, FKBP1, AGER, NFKB1, ALDH5A1, and GPIHBP1) that positively correlated with AS risk, while two proteins (AIF1 and ACOT13) showed inverse associations. Colocalization analysis confirmed shared causal variants between these proteins and AS for five of the six proteins. A phenome-wide association study (PheWAS) was then performed to assess potential adverse effects of these druggable proteins. The results suggested that TNF, AGER, and ALDH5A1 may have significant therapeutic potential, while FKBPL and AIF1 may have more complex roles. The study highlights the importance of further research to understand the mechanisms and potential side effects of these targets in treating AS.This study conducted a proteome-wide Mendelian randomization (MR) analysis to identify therapeutic targets for ankylosing spondylitis (AS), a chronic inflammatory disorder. The researchers utilized plasma protein data from the UK Biobank Pharma Proteomics Project and AS genetic association study data from the Finnish database. They identified six plasma proteins (TNF, FKBP1, AGER, NFKB1, ALDH5A1, and GPIHBP1) that positively correlated with AS risk, while two proteins (AIF1 and ACOT13) showed inverse associations. Colocalization analysis confirmed shared causal variants between these proteins and AS for five of the six proteins. A phenome-wide association study (PheWAS) was then performed to assess potential adverse effects of these druggable proteins. The results suggested that TNF, AGER, and ALDH5A1 may have significant therapeutic potential, while FKBPL and AIF1 may have more complex roles. The study highlights the importance of further research to understand the mechanisms and potential side effects of these targets in treating AS.