PARP1-targeting PROTAC attenuates alcohol-associated liver injury and ileal epithelial damage.

Alcohol-associated liver disease (ALD) is driven by oxidative stress, inflammation, hepatocyte death, and intestinal barrier disruption, yet targeted pharmacological options remain limited. Here, we investigated LB23, a proteolysis-targeting chimera designed to degrade poly (ADP-ribose) polymerase 1 (PARP1), in cellular and mouse models of alcohol-associated liver injury. In HepaRG cells, LB23 induced CRBN- and proteasome-dependent PARP1 degradation, with a half-maximal degradation concentration of 62.4 nM. Under H2O2-induced oxidative injury, nanomolar LB23 improved cell viability, reduced reactive oxygen species accumulation and inflammatory gene expression, and limited apoptosis and γ-H2AX accumulation. These effects were accompanied by increased BCL-2 and reduced BAX, cleaved caspase-3, and cleaved PARP1 levels. In mice receiving a Lieber-DeCarli ethanol diet, daily intraperitoneal LB23 lowered serum alanine aminotransferase, aspartate aminotransferase, and total bile acid levels and alleviated hepatic histological injury and lipid accumulation. LB23 also reduced NOX1, NOX2, and CYP2E1 mRNA expression levels, restored Nrf2 mRNA abundance, and supported body weight recovery during continued ethanol exposure. In the ileum, LB23 preserved villous morphology and epithelial junctional ultrastructure and increased occludin, ZO-1, claudin-1, and E-cadherin transcript levels. Collectively, these findings demonstrate efficient PARP1 degradation by LB23 in HepaRG cells and show that LB23 exerts protective effects against hepatic oxidative injury, apoptosis, and ileal epithelial damage in ethanol-fed mice, supporting further evaluation of this degradation-based pharmacological strategy for ALD.