Experimental mRNA therapy dramatically extends treatment window for acetaminophen overdose in preclinical models
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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 an approach in an animal model that could eventually 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 much later than the currently available antidote.
Acetaminophen, the generic name for 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 the 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."
A protective pathway in liver cells
Because acetaminophen overdose damages the liver through intense oxidative stress, the researchers focused on SRXN1, a protein 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 determine 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 with elevated levels of it. After an overdose, the mice that 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 constitutes a newly identified protective mechanism that helps liver cells survive acetaminophen-induced oxidative stress.
mRNA treatment extends the window in mice
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 the nanoparticles 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 an overdose in mice, partial protection at two hours and no protection beyond that point.
Human treatment remains a distant goal
Xie stressed that although the work is in its preclinical stages—and human application is many steps away—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."
Publication details
Xie, Wen, Desulfinylation of the deubiquitinase USP7 by SRXN1 attenuates oxidative acute liver injury, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2620180123. doi.org/10.1073/pnas.2620180123
Journal information: Proceedings of the National Academy of Sciences
Clinical categories
Clinical pharmacologyGastroenterology Provided by University of Pittsburgh Who's behind this story?
Gaby Clark
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