Virtual screening identified flurbiprofen as a high-affinity binder for HYAL3, and molecular dynamics simulations demonstrated stable binding between them.<h4>Conclusion</h4>This study systematically identified and experimentally validated HYAL3, ADIPOQ, ZNF852, and SCD as core genes in PAH-CMP comorbidity and proposed flurbiprofen as a candidate therapeutic agent targeting HYAL3. Here, ZNF852 is linked to pulmonary arterial hypertension.