Exploring the potential mechanism of atorvastatin in regulating ferroptosis as a treatment for heart failure based on network pharmacology.

Abstract

Heart failure (HF) is a complex clinical syndrome influenced by diverse mechanisms of cellular demise. Recent findings indicate that ferroptosis also plays a role in the pathogenesis of HF. The present investigation utilized network pharmacology to investigate the suppressive impact of atorvastatin calcium (AC) on ferroptosis in a rat model of HF. The rats were categorized into three groups: the control group, the doxorubicin-induced group, and the doxorubicin (DOX)-induced group + AC-treated group. Echocardiography, enzyme-linked immunosorbent assay, and Western blotting were employed to evaluate cardiac structural and functional changes. Additionally, network pharmacology methods were utilized to ascertain the potential targets of AC and their interactions with regulatory genes associated with ferroptosis and HF. We identified four HF-related ferroptosis regulatory targets of AC: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1), tumor protein 53 (TP53), dipeptidyl peptidase 4 (DPP4), and glutathione peroxidase 4 (GPX4). Enrichment analysis revealed three signaling pathways influenced by AC in HF: ferroptosis, fluid shear stress and atherosclerosis, and lipid and atherosclerosis. This study indicated that AC can improve cardiac systolic dysfunction, reduce ventricular volume, and reverse myocardial remodeling in a doxorubicin-induced HF rat model. We highlight the role of ferroptosis in mediating this therapeutic effect through solute carrier family 7 member 11 (SLC7A11)/TP53 signaling pathway regulation and shed light on new directions for clinical treatment.