Morroniside Attenuates Doxorubicin‐Induced Cardiotoxicity by Activating the PI3K/AKT/Nrf2/HO‐1 Pathway to Inhibit Ferroptosis and Oxidative Stress
TL;DR
This study provided the first evidence for Mor's cardioprotective effects against DIC by attenuated DIC by suppressing ferroptosis and reducing oxidative stress via activation of the PI3K/AKT/Nrf2/HO‐1 signaling pathway.
Abstract
Cardiotoxicity induced by doxorubicin (Dox) significantly contributes to increased mortality among cancer patients, yet available pharmacological interventions remain scarce. Recent studies suggest that ferroptosis is a key mechanism in the development of Dox‐induced cardiotoxicity (DIC). Morroniside (Mor), an active iridoid glycoside isolated from Cornus officinalis, exhibits multiple pharmacological properties such as antioxidant, anti‐ferroptotic, and anti‐inflammatory activities. Given this multi‐target profile, Mor shows potential as a treatment option for reducing DIC. This work was designed to examine the association between Mor and DIC. In vivo DIC model, C57BL/J mice received 5 mg/kg/d Mor via oral gavage for 5 weeks. In vitro DIC model, H9c2 cells were exposed to 10 μM Mor over a 48‐h period. Cardiac injury markers were quantified in serum and cell culture supernatants. Biochemical assays, western blotting, cellular immunofluorescence, and DHE/ROS staining were employed to evaluate ferroptosis and oxidative stress. Mor administration substantially reduced the levels of cardiac injury biomarkers while simultaneously attenuating ferroptosis and oxidative stress in vivo. In cellular models, Mor exhibited potent anti‐ferroptotic and antioxidant effects through Nrf2 pathway activation. Further mechanistic studies identified PI3K/AKT pathway as the upstream regulator of Nrf2 activation in response to Mor treatment. Our study provided the first evidence for Mor's cardioprotective effects against DIC. Mechanistically, Mor attenuated DIC by suppressing ferroptosis and reducing oxidative stress via activation of the PI3K/AKT/Nrf2/HO‐1 signaling pathway.