North, Trista E.Babu, I. RameshVedder, Lea M.Lord, Allegra M.Wishnok, John S.Tannenbaum, Steven R.Zon, Leonard I.Goessling, Wolfram2019-10-142010North, T. E., I. R. Babu, L. M. Vedder, A. M. Lord, J. S. Wishnok, S. R. Tannenbaum, L. I. Zon, and W. Goessling. 2010. “PGE2-Regulated Wnt Signaling and N-Acetylcysteine Are Synergistically Hepatoprotective in Zebrafish Acetaminophen Injury.” Proceedings of the National Academy of Sciences 107 (40): 17315–20. doi:10.1073/pnas.1008209107.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41543122Acetaminophen (APAP) toxicity is the most common drug-induced cause of acute liver failure in the United States. The only available treatment, N-acetylcysteine (NAC), has a limited time window of efficacy, indicating a need for additional therapeutic options. Zebrafish have emerged as a powerful tool for drug discovery. Here, we developed a clinically relevant zebrafish model of APAP toxicity. APAP depleted glutathione stores, elevated aminotransferase levels, increased apoptosis, and caused dose-dependent hepatocyte necrosis. These outcomes were limited by NAC and conserved in zebrafish embryos. In a targeted embryonic chemical screen, prostaglandin E2 (PGE2) was identified as a potential therapeutic agent; in the adult, PGE2 similarly decreased APAP-associated toxicity. Significantly, when combined with NAC, PGE2 extended the time window for a successful intervention, synergistically reducing apoptosis, improving liver enzymes, and preventing death. Use of a wnt reporter zebrafish line and chemical genetic epistasis showed that the effects of PGE2 are mediated through the wnt signaling pathway. Zebrafish can be used as a clinically relevant toxicological model amenable to the identification of additional therapeutics and biomarkers of APAP injury; our data suggest combinatorial PGE2 and NAC treatment would be beneficial for patients with APAP-induced liver damage.en-USJournal Article2019-10-1410.1073/pnas.1008209107