Rutin alleviates pirarubicin-induced cardiotoxicity and enhances chemosensitivity in breast cancer

Dose-dependent cardiotoxicity restricts the clinical utility of pirarubicin (THP) in breast cancer. Rutin, a natural flavonoid, demonstrates potential cardioprotective and anticancer properties. However, the precise mechanisms underlying its dual benefits in THP-based chemotherapy are largely unknown.

We investigated the contribution of the miR-129-1-3p/GRIN2D axis in mediating the cardioprotective and chemosensitizing effects of rutin in breast cancer.

A dual-disease model was constructed using 4T1 mammary tumor-bearing BALB/c mice. The mice received THP (6 mg/kg/week) and were co-administered either rutin (100 mg/kg, oral gavage) or miR-129-1-3p agomirs (tail vein injection). Cardiac function, oxidative stress markers (malondialdehyde and superoxide dismutase), myocardial enzymes (lactate dehydrogenase and creatine kinase), calcium homeostasis, and tumor progression (tumor weight, hepatic metastasis, and apoptosis) were systematically evaluated.

Rutin significantly alleviated THP-induced cardiotoxicity, as evidenced by the amelioration of myocardial oxidative stress injury, reduction in cardiomyocyte apoptosis, and restoration of calcium homeostasis. It simultaneously potentiated the antitumor efficacy of THP by suppressing tumor growth, reducing hepatic metastasis, and increasing tumor cell apoptosis. Mechanistically, rutin upregulated myocardial and tumoral miR-129-1-3p expression. This microRNA directly targeted and suppressed GRIN2D (a key N-methyl-D-aspartate receptor subunit), thereby attenuating downstream oxidative stress and calcium excess in both heart and tumor tissues.

Rutin mitigates THP-induced cardiotoxicity and enhances chemotherapeutic efficacy via the novel miR-129-1-3p/GRIN2D pathway. Our data show miR-129-1-3p to be an essential mediator, and suggest that the rutin-miR-129-1-3p-GRIN2D axis is a favorable target for improving the safety and effectiveness of breast cancer chemotherapy.