Toosendanin induced hepatotoxicity via triggering PERK-eIF2α-ATF4 mediated ferroptosis

Area of Science:

• Biochemistry
• Cell Biology
• Toxicology

Background:

• Toosendanin (TSN), derived from Melia toosendan, possesses diverse bioactivities.
• Hepatotoxicity is a significant concern associated with TSN exposure.
• The precise mechanisms underlying TSN-induced liver damage require further elucidation.

Purpose of the Study:

• To investigate the role of ferroptosis in TSN-induced hepatotoxicity.
• To identify the molecular pathways involved in TSN-induced ferroptosis.
• To validate the findings in an in vivo model.

Main Methods:

• Hepatocytes were treated with TSN, and ferroptosis indicators (ROS, lipid-ROS, GSH, ferrous ion, GPX4) were measured.
• qPCR and Western blotting were used to analyze gene and protein expression, including the PERK-eIF2α-ATF4 pathway and TFRC.
• Male Balb/c mice were treated with TSN, followed by histological analysis (H&E, 4-HNE), MDA content measurement, and GPX4 protein analysis.

Main Results:

• TSN treatment induced ferroptosis in hepatocytes, evidenced by altered ferroptosis markers.
• TSN activated the PERK-eIF2α-ATF4 signaling pathway, leading to increased ATF3 and TFRC expression.
• TFRC mediated iron accumulation, contributing to ferroptosis.
• In vivo studies confirmed that ferroptosis and the PERK-eIF2α-ATF4 pathway are involved in TSN-induced hepatotoxicity.

Conclusions:

• TSN induces hepatotoxicity through ferroptosis, characterized by iron accumulation.
• The PERK-eIF2α-ATF4 signaling pathway plays a crucial role in mediating TSN-induced ferroptosis and hepatotoxicity.
• Targeting ferroptosis pathways may offer therapeutic strategies for TSN-induced liver injury.