# Natural product library screening identifies Darutigenol for the treatment of myocardial infarction and ischemia/reperfusion injury

## TL;DR

A natural compound called Darutigenol was found to protect the heart from injury caused by lack of blood flow and reperfusion, offering a new potential treatment for heart disease.

## Contribution

Darutigenol was identified as a novel natural product that protects heart cells by activating the AKT1 pathway, offering a new therapeutic candidate for ischemic heart diseases.

## Key findings

- Darutigenol promotes cardiomyocyte survival and proliferation under ischemic conditions.
- Darutigenol reduces apoptosis and ROS generation in ischemia/reperfusion injury models.
- Darutigenol activates the AKT1 pathway and improves cardiac function in mice with myocardial infarction.

## Abstract

Ischemic heart diseases are the leading cause of death worldwide due to the inability of regeneration of adult cardiomyocytes (CMs). Natural products from medical herbs are an important source of innovative drugs for many diseases including cardiovascular diseases.

In this study, we set out to screen novel small-molecule therapies from natural products to protect heart against ischemic injury.

High-throughput screening was performed using a natural product library to identify the potential small molecules which can promote survival of CMs under ischemic and ischemic/reperfusion conditions. In addition, myocardial infarction (MI) and ischemia/reperfusion (I/R) mice models were used to evaluate the in vivo effects of the screened candidate. We also applied various analysis including cell viability, qPCR, Western blot, immunofluorescent staining, echocardiography, Masson’s staining, TTC staining, and network pharmacology.

High-throughput screening showed that the small molecule compound Darutigenol (Dar), derived from the Chinese traditional herb Herba Siegesbeckiae, could significantly promote CM survival and proliferation under ischemic conditions. Moreover, I/R-induced CM apoptosis and ROS generation could be significantly reduced by Dar treatment. In addition, in vivo administration of Dar was able to attenuate MI- and I/R-induced cardiac injury in adult mice by decreasing fibrosis and apoptosis, thereby improving cardiac function. Network pharmacology analysis and molecule docking assay showed that Dar has the highest binding affinity with AKT1 protein. Western blotting assay further revealed that AKT1 activation was significantly enhanced by Dar administration in the infarcted hearts.

Our data revealed that the small molecule compound Dar, screened from the natural product library in this study, is capable of protecting heart against MI and I/R injury by activating AKT1 pathway. These findings enrich the natural product candidates for cardiovascular disease treatment and provide new insights into potential therapeutic agents for MI and I/R injury.