Ophiopogon japonicus polysaccharide reduces doxorubicin-induced myocardial ferroptosis injury by activating Nrf2/GPX4 signaling and alleviating iron accumulation.

Abstract

Doxorubicin (DOX) is a principal chemotherapeutic agent in the domain of oncological intervention. However, its clinical application is constrained due to its severe and irreversible side effects, particularly heart damage. Ferroptosis, characterized by iron accumulation and redox system imbalance, serves a key role in DOX‑induced cardiotoxicity. Ophiopogon japonicus polysaccharide (OJP) exhibits diverse pharmacological activities, including cardiovascular protection, and anti‑inflammatory, anti‑oxidative and immune regulatory effects. However, the role and mechanism of OJP in DOX‑mediated ferroptosis‑triggered injury in cardiomyocytes remain elusive. The present study aimed to assess the effect of OJP on DOX‑induced myocardial ferroptosis injury and to reveal its underlying anti‑ferroptosis mechanism. The detection of myocardial injury markers, such as LDH, indicated that OJP can ameliorate myocardial damage. Additionally, western blot analyses reveal that OJP decreases the expression levels of the ferroptosis‑related marker transferrin receptor 1 (TFR1) while simultaneously increasing expression levels of glutathione peroxidase 4 (GPX4) in a concentration‑dependent manner. Furthermore, fluorescence probe assays demonstrate that OJP not only reduces iron accumulation and oxidative stress but also inhibits the production of lipid peroxidation, as evidenced by a decrease in malondialdehyde (MDA) levels measured. In addition, OJP simultaneously decreased ferroptosis by enhancing mitochondrial function. Mechanistically, OJP attenuated ferroptosis by upregulating the endogenous key antioxidant factor nuclear factor erythroid 2‑related factor 2 (Nrf2), which in turn increased the expression of the downstream signaling molecule GPX4 and reduced the accumulation of the labile iron pool. Therefore, OJP may be a novel therapeutic intervention for DOX‑induced ferroptosis‑triggered myocardial injury.