Inhibiting thromboinflammation with a designed peptide that blocks the IL-1β-FXIa axis uncouples antithrombosis from bleeding risk.

The complex interplay between inflammation and coagulation drives thromboinflammatory disorders. While previous studies have shown that interleukin-1β (IL-1β) can induce a hypercoagulable state in response to tissue hypoxia and inflammation, the specific mechanisms of its action on the coagulation cascade remain unclear. Here, we demonstrate that IL-1β directly potentiates key coagulation factors (FXIa, FXa, thrombin, and kallikrein) to accelerate thrombosis. Mechanistically, IL-1β enhances FXIa enzymatic activity through specific binding to its exosite domain. Additionally, we established an IL-1β-FXIa interaction model, based on which the inhibitory peptide QK10 was derived to specifically disrupt their interaction interface and effectively block IL-1β's potentiation of FXIa. Critically, in multiple thrombosis models, QK10 exhibited significant antithrombotic efficacy at doses equal to low molecular weight heparin (LMWH). Notably, bleeding assays revealed a significantly lower bleeding risk with QK10 compared to LMWH. Notably, QK10 also demonstrated promising anti-stroke efficacy in ischemic stroke models. Taken together, these findings establish QK10 as a viable therapeutic candidate that targets the IL-1β-FXIa prothrombotic axis for disruption, features enhanced safety, and offers a new approach to treating thrombo-inflammatory conditions, including ischemic stroke.