Tanshinone-IIA Mediated Attenuation of Post-Infarction Myocardial Fibrosis via IL-33/ST-2 Signaling Changes in Rat Epicardial Adipose Tissue

Myocardial infarction (MI), a severe form of coronary artery disease, often results in myocardial fibrosis, a key contributor to cardiac dysfunction and heart failure. Epicardial adipose tissue (EAT) is increasingly implicated in cardiovascular pathology through cytokine-mediated modulation of cardiac function. Tanshinone IIA (TanIIA), a lipophilic compound derived from Salvia miltiorrhiza, exhibits anti-inflammatory, antioxidant, and anti-fibrotic properties. This study aimed to evaluate the therapeutic potential of TanIIA in attenuating post-MI myocardial fibrosis and to explore its underlying mechanisms using an integrative approach combining in vivo experiments and in silico analyses. A murine MI model was established, and molecular docking was employed to assess TanIIA binding to key components of the interleukin-33/growth stimulation expressed gene 2 (IL-33/ST2) signaling pathway. Our results showed that TanIIA treatment significantly enhanced cardiac function, reduced histological injury, and mitigated myocardial fibrosis, alongside decreased serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI). TanIIA also attenuated inflammatory responses and oxidative stress in the serum, myocardium, and EAT. Mechanistically, TanIIA downregulated IL-33 and ST2 expression, suppressed the myeloid differentiation factor 88 (MyD88)/nuclear factor kappa-B (NF-κB) pathway, and reduced transforming growth factor-β1 (TGF-β1) levels. In silico analyses further revealed that TanIIA exhibited strong binding affinities for IL-33, ST2, MyD88, and NF-κB p65, with the most stable interaction predicted for ST2. Collectively, these findings indicate that TanIIA alleviates MI-induced myocardial fibrosis by modulating EAT-associated inflammation and oxidative stress, potentially via multi-target inhibition of the IL-33/ST2 axis. These results support TanIIA as a promising therapeutic candidate for the management of post-infarction myocardial fibrosis.