A multidisciplinary research team has discovered that liver alterations associated with metabolic dysfunction–associated fatty liver disease (MASLD) can directly cause cognitive and neurological impairments, and that these effects can be reversed by a therapy exclusively targeting the liver. The findings, published in Science Advances, establish the existence of a “liver–brain axis” that is not only clinically relevant but also therapeutically actionable. The study, led by Dr. Malu Martínez-Chantar, Principal Investigator at the Liver Disease Laboratory at CIC bioGUNE, member of BRTA, and co-led by Teresa Cardoso Delgado, Ikerbasque Research Associate Professor at IIS Biobizkaia, demonstrates that animal models of diet-induced metabolic liver disease show alterations in social memory and sensory processing, accompanied by dysfunctions in the hippocampus, a key region for memory and learning.
Most promisingly, these alterations were reversed by treating the liver with an innovative siRNA-based therapy targeting CNNM4, a magnesium transporter altered in this hepatic condition, using a highly specific GalNAc-siRNA delivery system.
“Our work demonstrates that fatty liver and hepatic inflammation can directly affect the brain and behavior. This opens up an entirely new therapeutic avenue: treating the liver to improve cognitive function,” explains Malu Martínez-Chantar.
“Moreover, we show how cutting-edge molecular biology technologies and targeted therapies can have a real impact on brain function, combining precision and efficacy,” adds Teresa Cardoso Delgado.
This groundbreaking study was made possible thanks to unprecedented institutional collaboration, bringing together leading research groups such as those of Benedicto Crespo-Facorro (Translational Psychiatry, IBiS), Manuel Romero Gómez (SeLiver, IBiS), Ander Matheu (Cellular Oncology, IIS Biogipuzkoa), Javier Crespo (Digestive Diseases, IDIVAL), the Proteomics Platform at CIC bioGUNE, and Rubén Nogueiras (Physiology, CIMUS). It also involved five CIBER programs: CIBERer, CIBERSAM, CIBERobn, CIBERfes, and CIBERehd.