Experimental mRNA Therapy Protects Liver After Acetaminophen Overdose, Even Hours Later

Study Suggests Paradigm Shift in Acetaminophen Overdose Treatment

A recent study published in the Proceedings of the National Academy of Sciences suggests a paradigm shift in treating acetaminophen overdose, offering new hope for patients arriving at the hospital with severe liver injury. Researchers at the University of Pittsburgh demonstrated in an animal model that an experimental therapy based on messenger RNA can protect the liver even when administered much later than the critical window allowed by the standard antidote. This discovery could significantly extend the time available for doctors in the race against the clock, a frequent situation in emergency cases where every minute counts.

Acetaminophen Overdose Remains a Leading Cause of Liver Failure

Acetaminophen, known by the brand name Tylenol, is one of the most widely used medications globally for treating pain and fever. Although considered safe when taken as directed, the risk becomes significant in cases of misuse, especially when people accidentally consume multiple over-the-counter products containing the same active ingredient. Overdose with this analgesic is an extremely common cause of emergency hospitalizations for liver failure, representing a serious clinical problem. Wen Xie, professor of pharmaceutical sciences at the University of Pittsburgh School of Pharmacy and the study’s lead author, emphasizes the gravity of this situation.

SRXN1 Protein Identified as Key Protector Against Oxidative Stress

The mechanism by which acetaminophen affects the liver involves intense oxidative stress. For this reason, the research team focused on the protein SRXN1, a cellular factor known for its ability to reverse oxidative damage. Although SRXN1 had been investigated previously in the context of other conditions, its specific role in acetaminophen-induced liver injury remained unexplored until now. By analyzing liver tissue samples from patients who died following an overdose, the researchers observed increased levels of SRXN1 during the deterioration process. To determine whether this protein was merely an associated marker or an active protective factor, they created two genetically modified mouse strains: one that did not express SRXN1 at all and another with amplified expression of this protein. The results were clear: mice lacking the protein suffered much more severe liver injury, while those with high levels benefited from considerable protection.

Using advanced protein mapping techniques, the team identified the exact causal chain: SRXN1 protects another protein called USP7, which in turn stabilizes the antioxidant molecule HO-1. This ensemble, now known as the SRXN1-USP7-HO-1 pathway, constitutes a newly identified protective mechanism essential for the survival of liver cells in the face of oxidative stress generated by acetaminophen. To exploit this pathway therapeutically, the researchers used lipid nanoparticles, the same delivery technologies that made possible mRNA-based COVID-19 vaccines. These nanoparticles were used to package the messenger RNA encoding for SRXN1 and were administered to mice subjected to overdose.

SRXN1-USP7-HO-1 Pathway Reveals Novel Protective Mechanism

The crucial difference from current treatment lies in the timing of administration. The FDA-approved antidote, N-acetylcysteine, must be injected within the first hours to be effective. In the new experiments, lipid nanoparticle therapy remained effective even six hours after overdose. By comparison, in murine models, N-acetylcysteine offers complete protection only if given within one hour after ingestion, partial protection at two hours, and no effect whatsoever beyond that point. Xie emphasizes that although the work is still in the preclinical stage and human application has many steps ahead, the result marks an important step in a promising direction. He expresses enthusiasm for the therapeutic potential, noting that, to his knowledge, this is the first study demonstrating a dramatic extension of the therapeutic window through the delivery of a protective protein via lipid nanoparticles.

Therapy Effective Hours After Overdose, Unlike Current Antidote

Experience gained from COVID-19 vaccines has shown that mRNA technology acts rapidly, which is ideal for acute events like overdose.

International Team and Funding Support the Research

The study was conducted by an international team that includes, alongside the lead author, researchers from the University of Pittsburgh such as Mengyun Ke, Jong-Won Kim, Meishu Xu, Jingyuan Wang, Lingyi Liu, Syamprasad NP, Bin Yang, Xiaofei Wang, Huatian Li, Songrong Ren, and Song Li. Kate S. Carroll from Florida Atlantic University also contributed to the work. Funding was provided by the National Institutes of Health through grants DK135538, ES030429, and DK145468. Human liver samples were obtained through the Pittsburgh Liver Research Center, Cells Tissues & Models Core, supported by NIH grant 1P30DK120531.