ASGR1 is a promising target for lipid reduction in pigs with PON2 as its inhibitor.

Although the role of asialoglycoprotein receptor 1 (ASGR1) in lowering lipid levels is well established, recent studies indicate that ASGR1 inhibition can cause unexpected liver damage in pigs, raising a serious issue about whether ASGR1 can be a good target for treating ASCVD. Here, we utilized the CRISPR-Cas9 system to regenerate ASGR1-knockout pigs, who displayed decreased lipid profiles without observable liver damage. This was confirmed by the lower levels of serum ALT and AST, reduced expression of inflammation markers, and normal histological morphology. Also, we implemented immunoprecipitation combined with mass spectrometry (IP-MS) and discovered that paraoxonase-2 (PON2) can interact with and significantly degrade ASGR1 in a dose-dependent manner. This degradation reduced lipid levels in mice, accompanied by little inflammation. Our study highlights the effectiveness and safety of degrading ASGR1 to reduce lipid levels in pigs and provides a potential inhibitor of ASGR1.