2026-06-02T02:05:08Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1018842025-03-18T12:32:47Zcom_20.500.14352_14col_20.500.14352_15

Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury Marañón, Patricia Wu, Hanghang Cubero Palero, Francisco Javier Valverde, Ángela M. 612.017 ALK3 Acetaminophen Acute liver failure Bone morphogenetic proteins DMH2 Drug induced liver injury Ciencias Biomédicas Inmunología 24 Ciencias de la Vida 2412 Inmunología Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF. Depto. de Inmunología, Oftalmología y ORL Fac. de Medicina TRUE pub 2024-03-04T09:25:18Z 2024-03-04T09:25:18Z 2024-02-15 journal article VoR https://hdl.handle.net/20.500.14352/101884 2213-2317 10.1016/j.redox.2024.103088 eng Marañón P, Rey E, Isaza SC, Wu H, Rada P, Choya-Foces C, Martínez-Ruiz A, Martín MÁ, Ramos S, García-Monzón C, Cubero FJ, Valverde ÁM, González-Rodríguez Á. Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury. Redox Biol. 2024 Feb 15;71:103088. doi: 10.1016/j.redox.2024.103088. Epub ahead of print. PMID: 38401290; PMCID: PMC10902147. Attribution-NonCommercial 4.0 International http://creativecommons.org/licenses/by-nc/4.0/ open access application/pdf Elsevier