Marañón, PatriciaWu, HanghangCubero Palero, Francisco JavierValverde, Ángela M.2024-03-042024-03-042024-02-15Marañón 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: PMC10902147.2213-231710.1016/j.redox.2024.103088https://hdl.handle.net/20.500.14352/101884Acetaminophen (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.engAttribution-NonCommercial 4.0 Internationaljournal articlehttps://pubmed.ncbi.nlm.nih.gov/38401290/https://pubmed.ncbi.nlm.nih.gov/38401290/open access612.017ALK3AcetaminophenAcute liver failureBone morphogenetic proteinsDMH2Drug induced liver injuryCiencias BiomédicasInmunología24 Ciencias de la Vida2412 Inmunología