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Experimental mRNA Therapy Dramatically Extends Treatment Window for Acetaminophen Overdose in Preclinical Models
PITTSBURGH – When a patient arrives at the hospital with an acetaminophen overdose, it’s often a race against the clock. The only FDA-approved antidote for overdose-related liver injury, N ‑acetylcysteine, must be administered within hours to be effective.
But in a new study published today in PNAS , researchers used a novel approach in an animal model that could eventually help buy more time for these patients. A team of University of Pittsburgh researchers identified a previously unrecognized liver-protection pathway—and harnessed it with an experimental mRNA therapy that reduced liver injury in mice, even when given at a much later point in time than the currently available antidote.
Acetaminophen, the generic form of Tylenol, is among the most widely used medications to manage pain and fever. While safe when taken as directed, it becomes dangerous when misused, such as when people accidentally take multiple over-the-counter medications that contain this drug.
“Acetaminophen overdose is a very common cause of emergency room visits for liver failure,” said Wen Xie, M.D., Ph.D., Joseph Koslow Endowed Chair and professor of pharmaceutical sciences at Pitt School of Pharmacy and senior author of the study. “It’s a serious clinical problem.”
Because acetaminophen overdose damages the liver through intense oxidative stress, the researchers focused on SRXN1, a protein that’s known to help cells reverse oxidative damage. Although SRXN1 had been studied in other diseases, its role in acetaminophen-induced liver injury had never been explored.
The researchers analyzed liver samples from patients who had died of acetaminophen overdose and found that SRXN1 levels increased during the injury process. To understand whether the protein was merely associated with liver damage or actively protecting against it, they genetically engineered two strains of mice, one lacking SRXN1 and another boosting it. When exposed to overdose, the mice who lacked the protein experienced significantly more severe liver injury—while the mice with elevated SRXN1 were protected.
Using advanced protein-mapping techniques, the team discovered that SRXN1 protects another protein, called USP7, which in turn stabilizes HO-1, a well-known antioxidant-defense molecule. Together, this SRXN1-USP7-HO-1 pathway comprises a newly identified protective mechanism that helps liver cells survive acetaminophen-induced oxidative stress.
To harness this mechanism and advance the treatment of acetaminophen overdose, the researchers used lipid nanoparticles—the same delivery technology that helped make mRNA COVID-19 vaccines possible—to package SRXN1 mRNA, and administered them in mouse models of acetaminophen overdose.
In these experiments, the treatment remained effective when administered to the mice six hours after an overdose. By comparison, the currently available antidote provides complete protection when given one hour after overdose in mice, partial protection at two hours and no protection beyond that point.
Xie stresses that, though the work is in its preclinical stages—and human application is many steps beyond—the findings represent the first step in a promising new direction.
“What really gets me excited is the therapeutic potential. To my knowledge, this is the first study showing that we can dramatically extend the therapeutic window through lipid nanoparticle delivery of mRNA coding for a protective protein,” he said.
“We learned from the COVID vaccines that mRNA can act very quickly, and that's exactly what we need for an acute event like overdose.”
Other authors on the study were Mengyun Ke, Jong-Won Kim, Meishu Xu, Jingyuan Wang, Lingyi Liu, Syamprasad NP, Bin Yang, Xiaofei Wang, Huatian Li, Songrong Ren and Song Li, all of Pitt; and Kate S. Carroll, of Florida Atlantic University.
This research was supported by the National Institutes of Health (DK135538, ES030429 and DK145468).
Human liver samples were acquired through the Cells Tissues & Models Core of the Pittsburgh Liver Research Center, supported by NIH grant 1P30DK120531.
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The University of Pittsburgh School of Pharmacy has been developing leaders who have been driving the future of pharmacy for over 135 years. We investigate, discover and create ways to improve patient health and, through partnerships, change practice and improve efficiency of care. Pitt Pharmacy ranks in the top 10 in NIH-funded research and in the top 15 in U.S. News and World Report among schools of pharmacy. The School of Pharmacy leads the way in education, personalizing education and getting students to expert faster. Chartered in 1878, the School of Pharmacy is among the oldest pharmacy schools in the country.
Proceedings of the National Academy of Sciences
Experimental study
Animals
Desulfinylation of the deubiquitinase USP7 by SRXN1 attenuates oxidative acute liver injury
28-Sep-2026
The authors declare no competing interest.