ASGR1 deficiency promotes liver injury by increasing GP73-mediated endoplasmic reticulum (ER) stress. ASGR1, a liver-specific lectin, is downregulated in patients with liver fibrosis or cirrhosis and in male mice with liver injury. ASGR1 deficiency exacerbates acetaminophen (APAP)-induced acute and CCl4-induced chronic liver injuries, while its overexpression mitigates these injuries. Mechanistically, ASGR1 binds to GP73, a mediator of ER stress, and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels, promoting its interaction with BIP and activating ER stress, leading to liver injury. Neutralizing GP73 alleviates liver injury and improves survival in APAP-intoxicated mice. These findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target. ASGR1 deficiency activates ER stress by disrupting the balance of circulating glycoproteins, leading to liver injury. ASGR1 facilitates the endocytosis and lysosomal degradation of GP73, reducing its levels and mitigating ER stress. Neutralization of GP73 reduces liver injury and improves survival in ASGR1-deficient mice. ASGR1 deficiency is associated with increased GP73 levels and hepatic ER stress in cirrhotic patients. These results highlight the role of ASGR1 in liver injury and suggest that targeting the ASGR1-GP73 axis could be a promising therapeutic strategy for liver injury.ASGR1 deficiency promotes liver injury by increasing GP73-mediated endoplasmic reticulum (ER) stress. ASGR1, a liver-specific lectin, is downregulated in patients with liver fibrosis or cirrhosis and in male mice with liver injury. ASGR1 deficiency exacerbates acetaminophen (APAP)-induced acute and CCl4-induced chronic liver injuries, while its overexpression mitigates these injuries. Mechanistically, ASGR1 binds to GP73, a mediator of ER stress, and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels, promoting its interaction with BIP and activating ER stress, leading to liver injury. Neutralizing GP73 alleviates liver injury and improves survival in APAP-intoxicated mice. These findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target. ASGR1 deficiency activates ER stress by disrupting the balance of circulating glycoproteins, leading to liver injury. ASGR1 facilitates the endocytosis and lysosomal degradation of GP73, reducing its levels and mitigating ER stress. Neutralization of GP73 reduces liver injury and improves survival in ASGR1-deficient mice. ASGR1 deficiency is associated with increased GP73 levels and hepatic ER stress in cirrhotic patients. These results highlight the role of ASGR1 in liver injury and suggest that targeting the ASGR1-GP73 axis could be a promising therapeutic strategy for liver injury.