Abstract: Acute-on-chronic liver failure (ACLF) was an acute decompensation of liver function occurring on a background of chronic liver disease, which was characterized by systemic inflammatory response and multiple organ failure and with an extremely high short-term mortality rate. Currently, apart from liver transplantation, there were no specific treatments and there was still a signif icant gap in therapeutic approaches for ACLF. This article systematically reviewed three major frontier directions in the treatment of ACLF: ① In terms of targeted therapy, it focused on the mechanisms and research progress of emerging targets such as pyruvate dehydrogenase kinase 4, let-7a-5p, semaphorin 6B and N-acetylgalactosamine (GalNAc)-lipid nanoparticle (LNP)-mitogen-activated protein kinase kinase 4-siRNA (siMKK4); ②Regarding artif icial liver support systems, it systematically elaborated the technological evolution from non-bioartif icial liver support system (plasma exchange, hemoperfusion, double plasma molecular adsorb system, versatile plasma purif ication system) to bioartif icial liver support system; ③ Exploration of new liver transplantation techniques (ischemia-free liver transplantation, ABO-incompatible livingdonor liver transplantation), aiming to provide references for clinical treatment decisions and future research directions in ACLF.