Sacubitril/Valsartan for Breast Cancer Therapy-Related Cardiac Dysfunction: An Integrated Meta-Analysis and Bioinformatics Study

Background Sacubitril/valsartan has proven efficacy in heart failure with reduced ejection fraction, but its role in breast cancer therapy-related cardiac dysfunction (CTRCD) remains unclear. We evaluated its efficacy and therapeutic targets via integrated meta-analysis and bioinformatics. Methods We systematically searched PubMed, Embase, Cochrane, Web of Science, and CNKI for sacubitril/valsartan studies in breast cancer CTRCD and performed meta-analysis. Candidate targets from network pharmacology were intersected with GEO differentially expressed genes; LASSO and SVM-RFE identified core targets. Two-sample Mendelian randomization assessed causality, and molecular docking verified binding. Results The meta-analysis included 7 studies (n = 409). In patients with established CTRCD, sacubitril/valsartan treatment significantly improved LVEF from baseline (MD = 5.27, 95% CI: 1.35–9.20, P = 0.008) and reduced NT-proBNP (MD=-2323.96, 95% CI: -4370.12 to -277.79, P = 0.03); in those with normal baseline cardiac function, LVEF also improved (MD = 1.30, 95% CI: 0.04–2.56, P = 0.04), and the incidence of CTRCD decreased (RR = 0.11, 95% CI: 0.01–0.93, P = 0.04). Mechanistically, machine learning identified 9 core therapeutic targets from 141 candidate targets. Mendelian randomization suggested causal associations of PIK3CG (OR = 0.88, 95% CI: 0.81–0.97, P = 0.006) and KEAP1 (OR = 1.12, 95% CI: 1.01–1.24, P = 0.028) with heart failure as a clinical endpoint of CTRCD. Molecular docking showed binding energies between sacubitril/valsartan and the above targets ranging from − 5.7 to -10.0 kcal/mol. Conclusions Sacubitril/valsartan improves cardiac function in both therapeutic and preventive settings of breast cancer CTRCD, with PIK3CG and KEAP1 as potential cardioprotective targets. Functional experiments and larger randomized trials are needed to confirm these findings.