# Aqueous Extract of Fructus Choerospondiatis Peel Suppresses Vascular Inflammation and Alleviates Atherosclerosis via AKT/c-FOS/IL-6 Axis

## TL;DR

A water extract from Fructus Choerospondiatis peel reduces inflammation and atherosclerosis in mice by targeting the AKT/c-FOS/IL-6 pathway.

## Contribution

The study identifies ellagic acid in FC peel as a bioactive compound that inhibits atherosclerosis via the AKT/c-FOS/IL-6 axis.

## Key findings

- FC peel extract reduces serum IL-6, plaque area, and macrophage content in atherosclerosis models.
- Ellagic acid is identified as the major bioactive component targeting AKT to suppress inflammation.
- FC peel extract shows broad anti-inflammatory effects across multiple models in mice.

## Abstract

Background: Atherosclerosis is the pathological basis for lethal cardio-cerebral vascular diseases, such as coronary artery disease and stroke. Fructus Choerospondiatis (FC) has demonstrated cardiac protective effects in multiple ethnomedicine. Whether these protective effects are attributed to the prevention of vascular atherosclerosis, however, remains unknown. We aim to examine the anti-atherosclerotic effect of FC aqueous extract and elucidate the underlying mechanism. Methods: FC was separated into peel and pulp, and the aqueous extract was obtained separately by boiling in water to mimic decocting. Atherosclerosis model was established in ApoE−/− mice fed with a high-fat diet, and histological analysis were utilized to evaluate the development of atherosclerosis. Various inflammatory models were constructed in mice to evaluate the anti-inflammatory effect of FC extract systemically, including acute local inflammation induced by traumatic injury (ear/foot swelling), acute systemic inflammation triggered by pathogenic infection (LPS- and POLY (I:C)-induced), as well as chronic inflammatory conditions associated with oxidative stress (D-galactose-induced), metabolic disorder (db/db mice), and aging. LC-MS and network pharmacology identified bioactive components and targets. Western blotting, ELISA, qPCR, and immunofluorescence were utilized to analyze the key genes involved in the mechanisms. Results: FC peel extract reduced serum IL-6 level, atherosclerotic plaque area, and macrophage content in the plaque, while pulp extract showed no protective effects. Peel extract exhibits anti-inflammatory effects in all models. The integrative application of LC-MS and network pharmacology identified ellagic acid as the major bioactive component and AKT as its target protein. Mechanistically, FC peel extract inhibits AKT phosphorylation, suppresses c-FOS expression and nuclear translocation, reduces IL-6 transcription and inflammation, and thus alleviates atherosclerosis. Conclusions: FC peel aqueous extract exerts anti-atherosclerotic effect by inhibiting inflammation through AKT/c-FOS/IL-6 axis. This study provides novel insights into the protective effects against atherosclerosis of FC peel and highlights its potential application in the prevention and treatment of coronary artery diseases.