Lycopene inhibits doxorubicin-induced heart failure by inhibiting ferroptosis through the Nrf2 signaling pathway

Abstract

Aims

Lycopene (LYC) is a dietary nutrient that plays a protective role in various cardiovascular diseases. Doxorubicin (DOX)-induced cardiotoxicity is an important cause of poor prognosis in many cancer patients treated with anthracyclines. This study aims to investigate the protective effects of LYC against DOX-induced heart failure (HF) and specific underlying mechanisms.

Materials and methods

DOX was used to establish HF model in cardiomyocytes and C57BL/6J mice to assess the protection of LYC against DOX-induced HF on inflammation, oxidative stress, and ferroptosis.

Key findings

LYC ameliorated DOX-induced deterioration of cardiac function. Mechanistically, LYC reduced collagen content and fibrosis by inhibiting the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9. Additionally, LYC inhibited reactive oxygen species (ROS) production by upregulating antioxidant enzymes expression. LYC enhanced B-cell lymphoma 2 (Bcl-2), but reduced apoptosis positive cells by reducing tumor protein 53 (p53), Bcl-2 associated X protein (Bax), and cleaved-Caspase 3 (c-Casp3) levels. Besides, LYC reduced inflammatory cytokine levels through activating peroxisome proliferator activated receptor gamma (PPARγ). Moreover, LYC ameliorated DOX-induced ferroptosis both in vivo and in vitro. Furthermore, we showed that LYC inhibited DOX-induced ferroptosis via binding to nuclear factor-erythroid 2-related factor 2 (Nrf2) to enhance its expression.

Significance

LYC improved DOX-induced cardiac dysfunction by reducing oxidative stress and inflammation, which was contributed by the reduction of ferroptosis. At molecular levels, LYC ameliorated DOX-induced ferroptosis through activating the Nrf2 signaling pathway. These findings indicate the potential of LYC as a therapeutic option for HF treatment.