Citation: Rodríguez-Agudo, R.; Goikoetxea-Usandizaga, N.; Serrano-Maciá, M.; Fernández-Tussy, P.; Fernández-Ramos, D.; Lachiondo-Ortega, S.; González-Recio, I.; Gil-Pitarch, C.; Mercado-Gómez, M.; Morán, L.; et al. Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen. Antioxidants 2022, 11, 897. https:// doi.org/10.3390/antiox11050897 Academic Editor: Stanley Omaye Received: 29 March 2022 Accepted: 27 April 2022 Published: 30 April 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antioxidants Article Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen Rubén Rodríguez-Agudo 1,† , Naroa Goikoetxea-Usandizaga 1,† , Marina Serrano-Maciá 1 , Pablo Fernández-Tussy 1 , David Fernández-Ramos 1,2,3 , Sofía Lachiondo-Ortega 1 , Irene González-Recio 1 , Clàudia Gil-Pitarch 1 , María Mercado-Gómez 1 , Laura Morán 4 , Maider Bizkarguenaga 1,3 , Fernando Lopitz-Otsoa 1,3 , Petar Petrov 1,2,5,6 , Miren Bravo 1 , Sebastiaan Martijn Van Liempd 7 , Juan Manuel Falcon-Perez 7,8 , Amaia Zabala-Letona 9,10 , Arkaitz Carracedo 8,9,10,11 , Jose Vicente Castell 2,5,6 , Ramiro Jover 2,5,6 , Luis Alfonso Martínez-Cruz 1 , Teresa Cardoso Delgado 1 , Francisco Javier Cubero 2,4 , María Isabel Lucena 2,12,13 , Raúl Jesús Andrade 2,14 , Jon Mabe 15 , Jorge Simón 1,2, * and María Luz Martínez-Chantar 1,2, * 1 Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain; rrodriguez@cicbiogune.es (R.R.-A.); ngoikoetxea@cicbiogune.es (N.G.-U.); mserrano@cicbiogune.es (M.S.-M.); pablo.fernandeztussy@yale.edu (P.F.-T.); dfernandez.ciberehd@cicbiogune.es (D.F.-R.); slachiondo@cicbiogune.es (S.L.-O.); irecio@cicbiogune.es (I.G.-R.); cgil@cicbiogune.es (C.G.-P.); mmercado@cicbiogune.es (M.M.-G.); mbizcarguenaga@cicbiogune.es (M.B.); flopitz@cicbiogune.es (F.L.-O.); petar.petrov@ciberehd.es (P.P.); mbravo@cicbiogune.es (M.B.); amartinez@cicbiogune.es (L.A.M.-C.); tcardoso@cicbiogune.es (T.C.D.) 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain; jose.castell@uv.es (J.V.C.); ramiro.jover@uv.es (R.J.); fcubero@ucm.es (F.J.C.); lucena@uma.es (M.I.L.); andrade@uma.es (R.J.A.) 3 Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain 4 Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), 28040 Madrid, Spain; lmoran@ucm.es 5 Unidad de Hepatología Experimental, Health Research Institute Hospital La Fe, Av. Fernando Abril Martorell, 46026 Valencia, Spain 6 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Av. de Blasco Ibáñez 15, 46010 Valencia, Spain 7 Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain; smvanliempd@cicbiogune.es (S.M.V.L.);jfalcon@cicbiogune.es (J.M.F.-P.) 8 Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; acarracedo@cicbiogune.es 9 Cancer Cell Signaling and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain; azabala@cicbiogune.es 10 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 28029 Madrid, Spain 11 Traslational prostate cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Research Health Institute, 48903 Barakaldo, Spain 12 Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga—IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Malaga, Spain 13 UICEC IBIMA, Plataforma ISCiii de Investigación Clínica, 28020 Madrid, Spain 14 Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Malaga, Spain 15 IK4-Tekniker, 20600 Eibar, Spain;jon.mabe@tekniker.es * Correspondence: jsimon.ciberehd@cicbiogune.es (J.S.); mlmartinez@cicbiogune.es (M.L.M.-C.) † These authors contributed equally to this work. Abstract: Drug-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 Antioxidants 2022, 11, 897. https://doi.org/10.3390/antiox11050897 https://www.mdpi.com/journal/antioxidants