A proteome-wide Mendelian randomization study identifies therapeutic targets for ankylosing spondylitis (AS). The study used plasma proteins from the UK Biobank Pharma Proteomics Project and genetic data from the Finnish database to assess causal relationships between plasma proteins and AS risk. Six proteins—TNF, FKBPL, AGER, ALDH5A1, and GPIHBP1—were found to have a positive association with AS risk, while AIF1 and ACOT13 showed inverse associations. Colocalization analysis confirmed shared causal variants between these proteins and AS, suggesting they could be potential therapeutic targets. Phenome-wide association studies (PheWAS) revealed potential adverse effects of these targets. The study highlights the importance of identifying new therapeutic targets for AS, as current treatments have limited efficacy and significant side effects. The findings provide new insights into the pathogenesis of AS and may lead to more effective therapies. The study's strengths include the use of Mendelian randomization to reduce confounding factors and the inclusion of cis-pQTLs to improve the reliability of results. However, the study has limitations, including a focus on European participants and the use of limited data for instrumental variables. The results suggest that proteins such as TNF, FKBPL, AGER, ALDH5A1, and ACOT13 may be promising therapeutic targets for AS. The study also highlights the need for further research to understand the complex relationships between these proteins and AS.A proteome-wide Mendelian randomization study identifies therapeutic targets for ankylosing spondylitis (AS). The study used plasma proteins from the UK Biobank Pharma Proteomics Project and genetic data from the Finnish database to assess causal relationships between plasma proteins and AS risk. Six proteins—TNF, FKBPL, AGER, ALDH5A1, and GPIHBP1—were found to have a positive association with AS risk, while AIF1 and ACOT13 showed inverse associations. Colocalization analysis confirmed shared causal variants between these proteins and AS, suggesting they could be potential therapeutic targets. Phenome-wide association studies (PheWAS) revealed potential adverse effects of these targets. The study highlights the importance of identifying new therapeutic targets for AS, as current treatments have limited efficacy and significant side effects. The findings provide new insights into the pathogenesis of AS and may lead to more effective therapies. The study's strengths include the use of Mendelian randomization to reduce confounding factors and the inclusion of cis-pQTLs to improve the reliability of results. However, the study has limitations, including a focus on European participants and the use of limited data for instrumental variables. The results suggest that proteins such as TNF, FKBPL, AGER, ALDH5A1, and ACOT13 may be promising therapeutic targets for AS. The study also highlights the need for further research to understand the complex relationships between these proteins and AS.