Metabolic dysfunction–associated steatotic liver disease alters brain function and behavior: Insights from liver-targeted siRNA therapy
Year: 2025
Type: article
Abstract: Metabolic dysfunction–associated steatotic liver disease (MASLD), a liver-centric condition, is associated with cognitive impairment and sensorimotor alterations. However, it remains unclear whether MASLD is sufficient to drive central nervous system deficits. Here, using diet-induced mouse models, we showed that MASLD was associated with alterations in social memory, sensorimotor processing, and hippocampal function, including decreased parvalbumin-positive interneurons, reduced dendritic spine density, and diminished dentate gyrus neurogenesis and neuronal differentiation. Then, we selectively modulated liver metabolism through N -acetylgalactosamine small interfering RNA (siRNA) therapy against Cyclin M4 ( CNNM4 ), a magnesium transporter dysregulated in MASLD. Liver-specific intervention with siRNA- Cnnm4 reversed impaired social memory and sensorimotor processing in association with recovery of hippocampal synaptogenesis and mitochondrial function pathways, alongside activation of neurogenesis-associated transcriptional programs. Our findings demonstrate that liver pathology is sufficient to drive neurobehavioral and hippocampal dysfunction in MASLD. Hepatic-specific intervention restores brain function, strongly supporting the existence of a causal and therapeutically targetable liver-brain axis for MASLD-associated neurological complications.
Source: Science Advances
Authors: Teresa Cardoso Delgado, Celia Martín-Cuevas, Ana C. Sánchez Hidalgo, Antonio Gil Gómez, Claudia M. Rejano Gordillo, Jon Landa, Rocío Gallego Durán, Naroa Goikoetxea-Usandizaga, Irene González-Recio, Clàudia Gil-Pitarch, L. Estefanía Zapata-Pavas, Jon Ander Barrenechea-Barrenechea, Carolina Conter, Luis Alfonso Martínez-Cruz, Víctor D. Ramos Herrero, Rubén Nogueiras, Mikel Azkargorta, Felix Elortza, Verónica Moncho-Amor, Javier Crespo, Ander Matheu, Manuel Romero Gómez, Benedicto Crespo-Facorro, María Luz Martínez-Chantar
Institutions: Ikerbasque, Centre for Biomedical Network Research on Rare Diseases, CIC bioGUNE, Consejo Superior de Investigaciones Científicas, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Biogipuzkoa Health Research Institute, Universidade de Santiago de Compostela, Xunta de Galicia, Center for Research in Molecular Medicine and Chronic Diseases, Centro de Investigación Biomédica en Red, Instituto de Investigación Sanitaria de Santiago, Universidad de Cantabria, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: G2262748287, G3480869486, G425668148, G5635532810, Dianas terapeuticas y biomarcadores para la medicina de precision en MAFLD (PreMed-MAFLD), Alteración de la barrera hematoencefálica en la esquizofrenia: bases moleculares de la vulnerabilidad o la resistencia, G7608361056, G7863371703, G8497050386
OpenAlex ID: W4415440469