Design of a Highly Active Peptide Inhibitor of Farnesyltransferase and Its Protective Effect Against Acute Liver Failure.

PURPOSE: Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. Previous studies have found that Farnesyltransferase (FTase) inhibitors improve disease progression in mouse models of endotoxemia, sepsis, and autoimmune hepatitis. PANoptosis is a novel type of programmed cell death (PCD), including pyroptosis, apoptosis, and necrosis, that plays an important role in ALF. This study was designed and investigated whether the FTase inhibitor PD083176 (d2,d3,d5) could attenuate ALF progression by modulating PANoptosis. METHODS: Combining the technical tools of computational biology, structural biology and pharmacology, we designed and obtained three high-affinity human FTase inhibitors of PD083176(d2,d3,d5). Then, these FTase inhibitors were investigated by animal experiments by administering PD083176(d2,d3,d5) (10 mg/kg) before modeling with LPS (100 μg/kg)/D-GalN (300 mg/kg) or TAA (800 mg/kg). RESULTS: We found that ALF induced by LPS/D-GaIN or TAA were associated with increased farnesylated protein in the liver. PD083176(d2,d3,d5) not only inhibited hepatic farnesylated proteins but also significantly attenuated liver injury and mortality in ALF mice. Importantly, PD083176(d2,d3,d5) treatment effectively inhibited hepatocyte apoptosis (Bax, Bcl-xL and TUNEL cell counts), pyroptosis (Caspase-1 and GSDMD), and necrotic apoptosis (RIPK1 and RIPK3). CONCLUSION: Collectively, these findings demonstrate that PD081376(d2,d3,d5) could alleviate LPS/D-GaIN or TAA-induced ALF by regulating apoptosis, pyroptosis, and necrotizing apoptosis, which might provide a new therapeutic strategy and scalability challenge for ALF.