HK4

HK4 is a novel, peripherally restricted small molecule positive allosteric modulator (PAM) of the gamma-aminobutyric acid type A (GABAA) receptor. It is a thioacrylamide-derivative specifically designed to be devoid of blood-brain barrier (BBB) penetration, thereby avoiding central nervous system effects typically associated with GABAergic modulation. HK4 is being investigated for its potential to protect human hepatocytes against lipotoxicity-induced injury, a key factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). By enhancing GABAergic signaling in the liver, HK4 reduces palmitate-induced apoptosis, inflammation, DNA damage, and endoplasmic reticulum (ER) stress. Preclinical studies have demonstrated its efficacy in reducing caspase 3/7 activity and cleaved PARP-1 expression in both HepG2 cells and human primary hepatocytes.