A recent study published in The American Journal of Pathology has identified MET (hepatocyte growth factor receptor) signaling as a crucial protective mechanism against acetaminophen-induced acute liver failure (ALF). Researchers found that the MET pathway serves a dual purpose by both minimizing liver damage and promoting regeneration following overdose.
Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is among the most widely used over-the-counter pain relievers and fever reducers globally. Despite its common use, overdoses—whether accidental or intentional—are a leading cause of drug-induced liver injury and account for nearly half of ALF cases in the United States each year. Approximately 80,000 cases related to APAP overdose are treated in hospitals annually. Recovery from this type of liver injury largely depends on the organ's capacity to regenerate.
While previous research established that MET signaling plays an important role in liver regeneration after surgical removal of part of the organ, its specific impact during toxic injuries like those caused by acetaminophen had not been well understood. In this study, scientists investigated how removing MET specifically from hepatocytes affects both injury severity and regenerative response after APAP overdose using a mouse model.
Lead investigator Bharat Bhushan, PhD, from the Department of Pathology at the University of Pittsburgh School of Medicine and Pittsburgh Liver Research Center, stated: "We found that MET deficiency dramatically worsened APAP overdose-induced liver injury by allowing toxic stress signals (c-Jun N-terminal kinase; JNK) to attack the mitochondria, the cell's metabolic hubs. Crucially, the absence of MET also severely impaired the liver's regeneration. By activating survival pathways like AKT (protein kinase B), we were able to reduce this damage, proving that MET is essential for both protecting and repairing the liver after a drug-induced overdose. Importantly, our analysis of human acute liver failure datasets confirms that these findings are clinically relevant."
Currently available treatments for acetaminophen-induced ALF are limited. N-acetyl cysteine (NAC) remains the only approved medication but is ineffective for patients who seek care late—a majority in clinical practice. When NAC does not work due to rapid disease progression or delayed treatment, liver transplantation becomes necessary but is constrained by donor availability. As a result, about 30% of such ALF cases lead to death.
First author Siddhi Jain from the same institutions commented: "There is an urgent need for novel therapies that go beyond the time window when NAC is effective. Our research is novel because it identifies MET signaling as a central pathway that not only restricts liver damage but also drives recovery, providing a promising dual therapeutic target. Every discovery brings us one step closer to better treatments for patients who need them most."
