DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis

Area of Science:

• Hepatology
• Pharmacology
• Molecular Biology

Background:

• Nonalcoholic steatohepatitis (NASH) is a progressive liver disease linked to obesity, characterized by fat accumulation, inflammation, and cell death, leading to fibrosis and cirrhosis.
• Current understanding of NASH mechanisms is limited, and effective treatments are lacking.
• DWN12088, a prolyl-tRNA synthetase (PRS) inhibitor, is known to suppress collagen synthesis but its role in NASH is unclear.

Purpose of the Study:

• To investigate the therapeutic potential and underlying mechanisms of DWN12088 in nonalcoholic steatohepatitis (NASH) progression.
• To elucidate the molecular pathways targeted by DWN12088 in liver injury and fibrosis.

Main Methods:

• Mice were fed a methionine-choline deficient (MCD) diet and treated with DWN12088 or saline for 6 weeks.
• Pathophysiological changes were assessed using molecular and biochemical techniques, including qPCR, immunoblotting, and immunohistochemistry.
• In vitro cell cultures were used to investigate molecular and cellular mechanisms of hepatic injury.

Main Results:

• DWN12088 mitigated palmitic acid-induced lipid accumulation and lipoapoptosis by downregulating key signaling pathways (ROCK/AMPK/SREBP-1c and PERK/eIF2α/ATF4/CHOP).
• DWN12088 inhibited pro-inflammatory gene expression by reducing NF-κB phosphorylation and suppressed pro-fibrotic gene expression via TGFβR1 signaling pathways.
• In MCD-diet-induced NASH mice, DWN12088 significantly reduced hepatic steatosis, inflammation, lipoapoptosis, and fibrosis progression.

Conclusions:

• DWN12088 demonstrates significant hepatoprotective effects in NASH models.
• The drug acts by modulating multiple signaling cascades involved in lipid metabolism, inflammation, and fibrosis.
• DWN12088 shows promise as a novel, integrated therapeutic agent for treating nonalcoholic steatohepatitis.