Hepatocyte cellular repressor of E1A-stimulated genes 1 protects against acetaminophen-induced liver injury by promoting autophagy.

Acetaminophen-induced liver injury (AILI) accounts for a significant proportion of acute liver failure emphasizing the critical need to elucidate AILI pathogenesis and to identify effective therapeutic agents. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that plays a crucial role in maintaining liver homeostasis. Prior studies have shown that CREG1 mitigates liver injury, steatosis, and inflammation associated with multiple liver diseases. In this study we investigated the role and therapeutic potential of CREG1 in AILI. We showed that the expression levels of CREG1 were markedly elevated in livers of AILI mice and patients with drug-induced liver injury (DILI), which was also observed in primary hepatocytes treated with acetaminophen (APAP). Hepatocyte-specific CREG1 deficiency mice were more sensitive to APAP compared to Creg1(fl/fl) mice, whereas AAV8-mediated CREG1 overexpression protected mice from AILI. We demonstrated that CREG1 deficiency impaired autophagy and activated inflammatory signaling pathways. Pre-administration of A769662 to activate AMPK or rapamycin to induce autophagy prevented the liver injury in Creg1(Δhep) mice. Coherently, the protective effect of CREG1 overexpression against AILI could be inhibited by dorsomorphin, an AMPK inhibitor. These findings suggest that CREG1 alleviates AILI by regulating autophagy through AMPK activation, and CREG1 represents a promising therapeutics target for AILI treatment.