Finerenone attenuates myocardial fibrosis in myocardial infarction complicated by chronic kidney disease: an integrated study combining network pharmacology, molecular simulations, and in vivo experiments.

چکیده اصلی

BACKGROUND: Myocardial infarction (MI) complicated by chronic kidney disease (CKD) is associated with adverse outcomes and exacerbated myocardial fibrotic remodeling. Finerenone is a non-steroidal mineralocorticoid receptor antagonist, but its effects and myocardial signaling changes in non-diabetic CKD-MI remain insufficiently characterized. METHODS: Network pharmacology identified candidate genes associated with finerenone and CKD-MI, and protein-protein interaction network topology prioritized candidate hub nodes. Molecular docking predicted finerenone-protein binding poses, while 100-ns molecular dynamics simulations characterized the conformational behavior of the modeled complexes under the applied simulation conditions. In a murine non-diabetic CKD-MI model, we assessed survival, left ventricular function, myocardial fibrotic remodeling, and myocardial EGFR, PI3K p85, and Akt phosphorylation. RESULTS: Among 188 overlapping candidate genes, eight candidate hub nodes were prioritized. The PI3K-Akt pathway was significantly enriched, with EGFR, PIK3CA, and PIK3R1 among the prioritized nodes. Predicted docking scores ranged from -8.6 to -7.3 kcal/mol, and modeled complexes exhibited stable conformational behavior under the applied simulation conditions. In vivo, finerenone improved 28-day survival (88.9% vs. 60.0% in vehicle-treated CKD-MI mice), preserved left ventricular systolic function, reduced myocardial collagen deposition and fibrotic marker protein levels, and lowered the phosphorylation-to-total protein ratios of EGFR, PI3K p85, and Akt. CONCLUSION: Finerenone exhibited cardioprotective and antifibrotic effects in a murine non-diabetic CKD-MI model. Integrated in silico and in vivo data suggest that the EGFR-PI3K-Akt axis is a candidate signaling pathway associated with these protective effects, although its causal contribution remains to be established.

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