# Protective Effects of COG133 on Carbon Tetrachloride‐Induced Acute Liver Injury: Modulation of Inflammation, Apoptosis and Sphingolipid Metabolism

## TL;DR

This study shows that COG133, a synthetic peptide, protects against liver damage caused by carbon tetrachloride by reducing inflammation, cell death, and restoring sphingolipid metabolism.

## Contribution

The novel contribution is demonstrating COG133's protective effects against CCl4-induced liver injury through modulation of inflammation, apoptosis, and sphingolipid metabolism.

## Key findings

- COG133 reduced liver damage, inflammation, and apoptosis in a CCl4-induced rat model.
- COG133 restored sphingomyelin and sphingosine-1-phosphate levels while lowering ceramide levels.
- COG133 lowered markers of inflammation and fibrosis, including TNF-α, NF-κB, and TGF-β.

## Abstract

Acute liver hepatotoxicity, characterised by inflammation, apoptosis and metabolic dysfunction, is often caused by drug‐induced toxic events. This study evaluated the protective effects of COG133, a synthetic peptide derived from apolipoprotein E (ApoE), against carbon tetrachloride (CCl4)‐induced liver damage, focusing on inflammation, apoptosis and sphingolipid metabolism. An acute hepatotoxicity model was established in rats utilising CCl4, with co‐administration of COG133 at varying doses. Histological analyses, immunostaining, messenger RNA (mRNA)/protein quantification, flow cytometry and mass spectrometry were employed to assess necroinflammation, apoptosis and sphingolipid levels. Cell viability assays and morphological evaluations were conducted on rat hepatocytes and hepatic stellate cells (HSC‐T6) to evaluate the protective effects of COG133. COG133 reduced liver damage, necroinflammation and apoptosis, restoring cell viability and lowering markers of inflammation, fibrosis and oxidative stress, including tumour necrosis factor‐alpha (TNF‐α), nuclear factor kappa‐B (NF‐κB), inducible nitric oxide synthase (NOS2), interleukin‐1 beta (IL‐1β), transforming growth factor‐beta (TGF‐β) and collagen type I (Col‐1). Immunostaining and molecular analyses confirmed these effects. Sphingomyelin (SM) and sphingosine‐1‐phosphate (S1P) levels were partially restored, while ceramide (CER) levels remained reduced in COG133‐treated groups. COG133 protects against CCl4‐induced liver injury by reducing inflammation, apoptosis and morphological damage, with partial restoration of sphingolipid metabolism. These findings support its potential as a novel therapeutic agent for acute liver injury.