# Epiafzelechin, a Flavanol, Regulates Lipid Homeostasis Through Modulation of HMGCR, PCSK9, and PPAR‐α: Mechanistic Insights and Therapeutic Implications

## TL;DR

Epiafzelechin, a natural flavanol, shows strong potential in managing high cholesterol by targeting key proteins involved in lipid metabolism.

## Contribution

The study provides mechanistic insights into how epiafzelechin modulates lipid homeostasis through multiple targets.

## Key findings

- Epiafzelechin significantly reduced cholesterol and triglyceride levels in a hyperlipidemic rat model.
- It exhibited better lipid-lowering effects than simvastatin with fewer liver side effects.
- Molecular docking confirmed strong binding to key lipid-regulating proteins like HMGCR and PCSK9.

## Abstract

Hyperlipidemia remains a leading modifiable risk factor for cardiovascular morbidity and mortality. Statins are considered the cornerstone of treatment; however, their adverse effects and limited efficacy in certain patient populations necessitate exploration of novel therapeutic avenues. Epiafzelechin (EZN), a flavanol with established antioxidant and anti‐inflammatory properties, was investigated for its potential role in lipid metabolism using an integrative approach combining network pharmacology, molecular docking, and in vivo validation. Putative EZN targets were predicted through SuperPred, Way2Drug, and PharmMapper, and intersected with hyperlipidemia‐related genes from GeneCards, DisGeNET, and CTD. Overlapping genes were subjected to protein–protein interaction (PPI) mapping, hub gene identification, and pathway enrichment analysis. Molecular docking was conducted to assess the binding affinity of EZN to lipid‐regulating proteins. Therapeutic efficacy of EZN was also evaluated in a TWR‐1339‐induced hyperlipidemic rat model using biochemical assays and real‐time PCR for gene expression profiling. A total of 105 genes were identified, involved in lipid transport, inflammatory signaling, and metabolic regulation. Functional enrichment and PPI analysis highlighted HMGCR, PCSK9, PPAR‐α, and LDLR as key targets. Docking studies revealed that EZN has strong binding affinities with these targets, supporting the structural feasibility of these interactions. In vivo, EZN treatment significantly reduced total cholesterol, triglycerides, LDL, and VLDL levels, while increasing HDL. Compared with simvastatin, EZN exhibited superior lipid‐lowering effects with a more favorable liver enzyme profile. Gene expression and ELISA analyses indicated downregulation of HMGCR, PCSK9, and APOB, and upregulation of PPAR‐α, LDLR, and SRB, highlighting its multi‐target modulation of lipid homeostasis. These findings indicate that EZN exerts broad regulatory effects on lipid metabolism through pleiotropic mechanisms and may represent a promising natural candidate for managing hyperlipidemia.