Direct Inhibition of Macrophage STING Signaling by Curcumol Protects Against Myocardial Infarction via Attenuating the Inflammatory Response

•Curcumol Ameliorates Post-MI Damage by inhibiting Macrophage Inflammation.•Curcumol Targets STING to Suppress Type I Interferon Response, Mitigating cardiac injury after MI.•Curcumol May be a Novel Natural Inhibitor for STING.•Inhibition of IFN-I response by curcumol involves STING-TBK1-IRF3 axis. : Macrophages play a crucial role in the pathological process after myocardial infarction (MI). However, pharmacological therapy targeting this pathway remains undefined. Curcumol, a natural compound extracted from the Curcumae Rhizoma, has demonstrated anti-tumor and anti-inflammatory activities. Therefore, this study aimed to explore the potential of curcumol as a therapeutic agent for MI. : Wild-type (WT) mice were administered with curcumol orally following left coronary artery ligation. The effects of curcumol on post-MI inflammatory responses were evaluated through phenotypic analysis, histology, and flow cytometry. RNA sequencing, surface plasmon resonance (SPR), and molecular docking were utilized to identify the molecular target of curcumol. Functional studies were further conducted using stimulator of interferon genes (STING) knockout (Sting-/-) mice. : Curcumol treatment improved the survival rate in mice following MI while enhancing cardiac function and mitigating adverse post-infarction ventricular remodeling. Transcriptomic analysis and SPR indicated curcumol directly bound to STING. Functional assays demonstrated that the cardio-protective effects of curcumol were mediated via STING, as these effects were diminished in Sting-/- mice. Mechanistically, curcumol disrupted STING-TBK1 interaction, suppressing downstream signaling activation and type I interferon responses. Notably, curcumol exhibited stronger inhibition of activated STING signaling in macrophages and superior cardioprotective effects compared to the STING inhibitor H-151. : Curcumol targets STING to suppress type I interferon responses, improving cardiac function post-MI. These findings highlight curcumol as a promising therapeutic candidate for MI treatment.