# Engeletin alleviates doxorubicin-induced cardiotoxicity via the AMPK pathway in mice

## TL;DR

Engeletin protects against heart damage caused by doxorubicin in mice by activating the AMPK pathway.

## Contribution

Engeletin is shown to alleviate doxorubicin-induced cardiotoxicity via AMPK pathway activation in both in vitro and in vivo models.

## Key findings

- Engeletin reduced apoptosis, oxidative stress, and mitochondrial damage in doxorubicin-treated cardiomyocytes and mice.
- AMPK pathway activation was identified as the key mechanism behind Engeletin's protective effects.
- Blocking the AMPK pathway with Compound C reversed the protective effects of Engeletin.

## Abstract

The extensively employed antineoplastic drug doxorubicin (DOX) is constrained in clinical utilization on account of its severe cardiotoxicity, and there persists a dearth of protective agents against doxorubicin-induced cardiotoxicity (DIC). Engeletin (ENG) is a natural product endowed with multiple biological activities and has manifested significant protective effects in various diseases. This study purports to explore the protective effects of ENG in DIC and elucidate the underlying mechanisms.

H9C2 cardiomyocytes and C57BL/6 mice were used to establish in vitro and in vivo models of DIC, and ENG was used for treatment. Cardiac function and structural changes in the mice were assessed by ultrasound, pathological section staining and transmission electron microscopy. Western blotting, Real-Time Quantitative PCR, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), serum biochemical detection, TUNEL staining, dihydroethidium (DHE) assay, and flow cytometry were employed to evaluate apoptosis, autophagy, oxidative stress, inflammation, mitochondrial damage, ANP and BNP both in vitro and in vivo. An AMPK inhibitor Compound C was utilized to validate the effect of ENG on the AMPK pathway.

DOX diminished cardiac function and induced fibrosis in mice, resulting in significant cell apoptosis, oxidative stress, inflammation, autophagy dysregulation, and mitochondrial damage both in vitro and in vivo. Following ENG treatment, these conditions can be markedly ameliorated, especially in mitigating myocardial cell apoptosis, autophagy, and oxidative stress responses. It has been found that this effect is realized through the activation of the AMPK pathway. Moreover, utilization of an AMPK inhibitor CC impeded the protective effect of ENG on DIC.

ENG has mitigated DIC through the activation of the AMPK pathway, thereby rendering it a potential drug for the prevention and treatment of DIC.