This study investigates the role of asialoglycoprotein receptor 1 (ASGR1) in liver injury. ASGR1, a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. The research shows that ASGR1 deficiency exacerbates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice, while its overexpression mitigates these injuries. Mechanistically, ASGR1 binds to GP73, a mediator of endoplasmic reticulum (ER) stress, and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels, promoting the interaction between GP73 and BIP, which activates ER stress and leads to liver injury. Neutralizing GP73 not only alleviates ASGR1 deficiency-induced liver injuries but also improves survival in mice treated with a lethal dose of acetaminophen. These findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for liver injury treatment.This study investigates the role of asialoglycoprotein receptor 1 (ASGR1) in liver injury. ASGR1, a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. The research shows that ASGR1 deficiency exacerbates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice, while its overexpression mitigates these injuries. Mechanistically, ASGR1 binds to GP73, a mediator of endoplasmic reticulum (ER) stress, and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels, promoting the interaction between GP73 and BIP, which activates ER stress and leads to liver injury. Neutralizing GP73 not only alleviates ASGR1 deficiency-induced liver injuries but also improves survival in mice treated with a lethal dose of acetaminophen. These findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for liver injury treatment.