Sesamin alleviates drug-induced hepatotoxicity via autophagy enhancement and ferroptosis inhibition.

BACKGROUND

Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. Sesamin (Ses), a natural polyphenolic compound, possesses diverse pharmacological properties. This study was to explore the effects of Ses on APAP-induced liver injury and the underlying molecular mechanism.

METHODS

In vivo, C57BL/6J mice were treated with different doses of Ses for 28 days. After overnight food deprivation, mice were intraperitoneally injected with a single dose of APAP. In vitro, the AML12 and HepG2 cells were pre-treated with Ses and then treated with APAP.

RESULTS

Ses dramatically alleviated APAP-induced hepatocellular injury in vitro and in vivo. Proteomic analysis suggested that the differentially expressed proteins were enriched in ferroptosis, autophagy, and FoxO signaling pathways between the APAP group and the Ses-treated groups. We subsequently found that ferroptosis was significantly inhibited, and autophagy was significantly enhanced in the Ses-treated group. Consistently, Ses obviously reduced the expression of Foxo1. However, hepatocyte-specific knockout Foxo1 abolished the effect of Ses on hepatocyte autophagy and ferroptosis caused by APAP in mice.

CONCLUSIONS

Our findings demonstrate that Ses attenuates APAP-induced hepatotoxicity through Foxo1, which mediates both the activation of autophagy and the inhibition of ferroptosis. It provides a new strategy for the prevention and treatment of drug-induced liver injury.