Role and mechanism of ASGR1 in acute liver injury.

AIMS: ASGR1 is a hepatocyte surface glycoprotein receptor that plays a crucial role in maintaining liver homeostasis. This study investigates its role in acute liver injury (ALI) and whether it is associated with the regulation of PANoptosis-like pathway.

MATERIALS AND

METHODS

An LPS/D-Gal-induced ALI model was established using ASGR1 knockout mice. Liver function, inflammation, oxidative stress, mitochondrial function, and PANoptosis-like markers were assessed. In vitro studies on primary hepatocytes examined the effects of ASGR1 knockout or overexpression on ALI, with the ROS inhibitor NAC and NOXs inhibitor DPI used to explore underlying mechanisms.

KEY FINDINGS: In the ALI model, ASGR1 expression was decreased, and ASGR1-/- mice showed lower survival, more severe liver injury, and higher inflammatory cytokine levels. Electron microscopy revealed pronounced cell death-associated morphological changes in ASGR1-/- hepatocytes under ALI. Using multiple cell death inhibitors, we confirmed that apoptosis and necroptosis were the predominant death modalities, consistent with increased BAX/BCL-2 ratio, cleaved caspase-8, p-RIPK1, p-RIPK3, and p-MLKL. Proteomic analysis revealed that the differentially expressed proteins were predominantly enriched in pathways related to oxidative stress and mitochondrial function. ASGR1 deficiency in ALI led to elevated ROS levels and a marked reduction in mitochondrial membrane potential, both of which were reversed by NOXs inhibition. Importantly, scavenging ROS and inhibiting NOXs substantially mitigated the activation of the PANoptosis-like pathway induced by ASGR1 deficiency.

SIGNIFICANCE: ASGR1 downregulation aggravates ALI via the NOXs-ROS-PANoptosis-like axis, underscoring the pivotal role of ASGR1 in ALI progression.