# MAGL-18c attenuates LPS-induced sepsis-associated liver injury by inhibiting TGF-β/Smad signaling and remodeling medium- and long-chain fatty acid metabolism

## TL;DR

MAGL-18c, a new drug, reduces liver damage in sepsis by blocking harmful inflammation and improving fatty acid metabolism.

## Contribution

MAGL-18c is a novel MAGL inhibitor shown to protect against sepsis-induced liver injury through TGF-β/Smad signaling inhibition and lipid metabolism remodeling.

## Key findings

- MAGL-18c suppresses TGF-β/Smad signaling and pro-inflammatory cytokine production in sepsis-induced liver injury.
- MAGL-18c improves liver histopathology and reduces neutrophil infiltration and hepatocyte apoptosis.
- MAGL-18c modulates unsaturated fatty acid metabolism and mitochondrial dysfunction in septic liver injury.

## Abstract

Sepsis is a major global health burden associated with high mortality and multiple organ dysfunction, among which liver injury is a key determinant of poor prognosis. However, effective therapeutic strategies for sepsis-associated liver injury (SALI) remain limited.

In this study, we investigated the protective effects of MAGL-18c, a novel monoacylglycerol lipase (MAGL) inhibitor, on lipopolysaccharide (LPS)-induced SALI. Hepatic inflammation, apoptosis, mitochondrial function, and lipid metabolism were assessed using liquid chromatography–mass spectrometry (LC-MS), Western blotting, real-time quantitative PCR (qPCR), immunohistochemistry, and other methods.

MAGL-18c markedly attenuated hepatic inflammation by suppressing TGF-β/Smad signaling and reducing pro-inflammatory cytokine production. Moreover, MAGL-18c significantly improved liver histopathology, reduced neutrophil infiltration, modulated unsaturated fatty acid metabolism, and alleviated hepatocyte apoptosis and mitochondrial dysfunction.

These findings indicate that MAGL-18c protects against LPS-induced SALI through coordinated regulation of inflammation, apoptosis, mitochondrial function, and lipid metabolism, highlighting its potential as a promising therapeutic candidate for sepsis-associated liver injury.