Inhibition of the Wnt/β-Catenin pathway via an LGK974-cyclodextrin inclusion complex alleviates cardiac injury

Cardiac hypertrophy and fibrosis arise from molecular, physiological, and immune alterations triggered by disorders such as myocardial infarction, myocarditis, and Chagas cardiomyopathy. The Wnt/β-catenin pathway is central to this remodeling. Here,we evaluated the therapeutic potential of a supramolecular complex of the Wnt/β-catenin inhibitor LGK974 and modified cyclodextrin (CD:LGK974) to attenuate cardiac injury in experimental model of Trypanosoma cruzi (T. cruzi)-induced cardiac damage. In vivo, Balb/c mice were intraperitoneally infected with 10 ³ T. cruzi trypomastigotes and treated with CD:LGK974 via oral gavage for 21 days under different dose regimes to assess its immunomodulatory, antifibrotic, and antihypertrophic activities. The treatment significantly reduced parasitemia, cardiac hypertrophy and fibrosis in the T. cruzi infection model compared to control groups. Immunofluorescence revealed downregulation of β-catenin in treated animals. Additionally, flow cytometry demonstrated proliferation of CD4⁺, CD8⁺, and NK cells, along with elevated IL-10 expression in NK⁺ cells, suggesting an immunomodulatory effect. These findings indicate that CD:LGK974 attenuates cardiac injury and modulates immune response in T. cruzi-infected mice. Together, these results highlight its potential as a therapeutic strategy for reducing pathological cardiac remodeling associated with T. cruzi infection.