PAI-1 as a Systemic Integrator Node: A Unified Relative Permissiveness Network Account of Genotype-Conditioned Aspirin Efficacy Across Multiple Cancers, Bacterial Vaccination, and Immune Checkpoint Biology

Background: Plasminogen activator inhibitor-1 (PAI-1, SERPINE1) is one of the most
widely validated prognostic biomarkers in oncology, endorsed by ASCO for treatment
decisions in node-negative breast cancer, and implicated in disease progression across
prostate, ovarian, endometrial, and multiple other cancers. The 4G/5G insertion-deletion
polymorphism at rs1799889 in the PAI-1 promoter produces constitutively higher PAI-1
expression in 4G/4G homozygotes, with a 25% baseline elevation that amplifies to up to
six-fold higher mRNA output under inflammatory stimulation with IL-1β. Despite this,
genotype has never been systematically examined as a conditioning variable for
treatment response.
Framework: We apply the Relative Permissiveness Network (RPN) framework