Abstract 4141714: Curcumol as a novel STlNG inhibitor suppresses type I interferon release to improve myocardial infarction

Background: Myocardial infarction is a leading cause of morbidity and mortality worldwide, often resulting in extensive myocardial cell death and the release of damage-associated molecular patterns. These DAMPs activate the Stimulator of Interferon Genes pathway, which subsequently induces the release of type I interferon and other pro-inflammatory cytokines, contributing to the inflammatory microenvironment and exacerbating cardiac dysfunction. Curcumol, a compound isolated from the traditional Chinese medicine zedoary turmeric, has demonstrated anti-inflammatory and anti-tumor properties. This study investigates the potential of Curcumol as a novel STING inhibitor to suppress type I interferon release and improve outcomes following MI. Methods: A mouse model of myocardial infarction was established by ligating the left anterior descending coronary artery in vivo. Mice were treated with curcumin, and cardiac function was assessed by echocardiography. Post-myocardial infarction, macrophages were isolated and subjected to RNA-Seq analysis, which revealed that IFNβ1 was the most significantly downregulated transcription factor. Surface plasmon resonance assays were conducted to detect the direct binding of curcumol to the STING protein and validated in vivo using STING knockout mice. In vitro experiments were performed to assess the effect of curcumol on STING oligomerization and transport, utilizing co-immunoprecipitation and immunofluorescence staining. Result: Curcumol treatment improved cardiac function in post-infarction mice, as evidenced by increased ejection fraction and reduced infarct size. In vitro, curcumol significantly reduced the release of type I interferons and the production of pro-inflammatory cytokines. Mechanistically, curcumol inhibited STING ER-to-Golgi translocation by suppressing STING oligomerization, thereby inhibiting STING-dependent pathway activation. Compared to H-151, curcumol demonstrated favorable inhibitory effects and may be a potential novel STING inhibitor. Conclusion: Our study demonstrates that Curcumol, a compound isolated from the traditional Chinese medicine zedoary turmeric, shows significant potential as a novel STING inhibitor. These findings suggest that Curcumol is a promising STING inhibitor for improving outcomes following myocardial infarction by targeting and modulating the STING pathway. Keywords: Curcumol, STING, Type I Interferon, Inflammation, myocardial infarction