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

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.