Rodríguez-Agudo, RubénGoikoetxea-Usandizaga, NaroaSerrano-Maciá, MarinaFernández-Tussy, PabloFernández-Ramos, DavidLachiondo-Ortega, SofíaGonzález-Recio, IreneGil-Pitarch, ClàudiaMercado-Gómez, MaríaMorán, LauraBizkarguenaga, MaiderLopitz-Otsoa, FernandoPetrov, PetarBravo, MirenVan Liempd, Sebastiaan MartijnFalcon-Perez, Juan ManuelZabala-Letona, AmaiaCarracedo, ArkaitzCastell, Jose VicenteJover, RamiroMartínez-Cruz, Luis AlfonsoDelgado, Teresa CardosoCubero, Francisco JavierLucena, María IsabelAndrade, Raúl JesúsMabe, JonSimón, JorgeMartínez-Chantar, María Luz2023-05-032023-05-032022-04-302076-3921http://hdl.handle.net/10668/20781Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/acetaminophen (APAP)ammoniadrug-induced liver injury (DILI)methionine cyclemiR-873-5pmitochondriapolyaminestherapyresearch article35624761open access10.3390/antiox11050897PMC9137496https://www.mdpi.com/2076-3921/11/5/897/pdf?version=1651326482https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137496/pdf