Lactoferrin alleviates doxorubicin-induced myocardial injury in mice: Associations with gut microbiota and microbial metabolites

Lactoferrin (LF), a bioactive glycoprotein derived from milk, has demonstrated cardioprotective potential. However, whether gut microbiota and their derived metabolites are associated with these cardioprotective effects remains to be elucidated. In this study, 24 male C57BL/6 mice were randomly assigned to control, doxorubicin (DOX), and LF+DOX groups (n = 8 each). Supplementation with LF alleviated DOX-induced myocardial injury, as evidenced by increased heart weight (0.16 ± 0.02 g), decreased serum cardiac troponin I (61.32 ± 17.85 ng/L), and partial normalization of electrocardiographic abnormalities. Compared with the DOX group, LF treatment shortened the QT interval by 19.47% ± 7.83% and the PR interval by 9.11% ± 3.04%, and reduced ST segment elevation by 29.32% ± 6.54%. Histological analysis revealed reduced myocardial fibrosis and apoptosis. At the molecular level, LF modulated the expression of proteins involved in mitochondrial dynamics (Mfn2, Drp1, Fis1) and mitophagy (PINK1). Additionally, LF altered the gut microbial composition and fecal metabolite profiles. Two tripeptides-LVD and FVD-were elevated in the LF+DOX group and demonstrated protective effects in H9C2 cardiomyoblast cell models. Although these findings suggest a possible role for gut microbial metabolites in mediating the cardioprotective effects of LF, further in vivo studies are needed to establish causality. These results support continued investigation of LF as a dairy-derived functional ingredient for cardiovascular health.