Metformin in the four-dose protocol could successfully protect against Cfz cardiotoxicity without interfering with Cfz proteasome inhibitory activity and independently of myocardial oxidative stress. Graphs of LLVY chemotrypsin-like activity % in the (A). PBMCs and (B). Heart expressed as fold change of young adult (13–14 weeks of age) C57BL/6J mice after four doses of Cfz (n = 7–9 per group). (C). Fasting blood glucose levels (mg/dL). (D) Myocardial MDA content (in mmol/mg protein, n = 5–7 per group). (E,F). Representative M-Mode images and graph of fractional shortening (FS%) in the four-dose protocol (n = 5–8 per group). Data are presented as mean ± SEM. One-Way ANOVA, Tukey post-hoc test, * p < 0.05, ** p < 0.01, *** p < 0.005, **** p < 0.001.