# Binankadsurin A from Kadsura coccinea Fruits Ameliorates Acetaminophen-Induced Liver Injury Through Inhibiting Oxidative Stress by Keap1/Nrf2/HO-1 Pathway

## TL;DR

A compound from Kadsura coccinea fruits protects the liver from acetaminophen damage by reducing oxidative stress through a specific biological pathway.

## Contribution

The first-time determination of Binankadsurin A's crystal structure and its novel mechanism of liver protection via the Keap1/Nrf2/HO-1 pathway.

## Key findings

- Binankadsurin A reduces liver injury by lowering AST and ALT levels in mice.
- The compound activates the Keap1/Nrf2/HO-1 pathway to combat oxidative stress.
- Molecular docking shows Binankadsurin A blocks Nrf2 binding to Keap1.

## Abstract

Objectives: Kadsura coccinea fruit is a traditional medicinal plant rich in dibenzocyclooctadiene lignans, with established hepatoprotective effects. Binankadsurin A (BKA), a dibenzocyclooctadiene lignan isolated from the K. coccinea fruits. This study aims to evaluate its hepatoprotective efficacy in an acetaminophen (APAP)-induced mouse liver injury model. Methods: The structure of BKA was elucidated by HR-ESI-MS, NMR, single-crystal X-ray diffraction and comparison of their data with those of the literature. Mice were randomly divided into five groups: Control, APAP (400 mg/kg, single intraperitoneal injection), APAP + bicyclol (50 mg/kg), APAP + low-dose BKA (50 mg/kg), and APAP + high-dose BKA (100 mg/kg). Untargeted metabolomics, immunohistochemistry, Western blot analysis, and molecular docking were performed. Results: BKA was determined as a dibenzocyclooctadiene lignan, and the single-crystal structure is reported for the first time. The untargeted metabolomics revealed that metabolites and pathways are closely associated with oxidative stress. In vivo studies showed that pretreatment with BKA can mitigate liver injury. BKA reduced serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and stored hepatic glutathione (GSH) levels. Immunohistochemical analysis results also showed that CYP2E1 expression in the mouse liver could be improved through BKA pretreatment. Furthermore, Western blot analysis presented that BKA could increase the protein expression of Nrf2, HO-1, and NQO-1. Additionally, molecular docking indicated that BKA directly blocks the binding site of Nrf2 with Keap1. Conclusions: BKA reduces APAP-induced acute liver damage by inhibiting oxidative stress by activating the Keap1/Nrf2/HO-1 signaling pathway, providing a theoretical basis for BKA as a potential therapeutic agent for APAP-induced liver injury.