Teresa C. 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 Darío Ramos‐Herrero, Rubén Nogueiras, Mikel Azkargorta, Félix Elortza, Verónica Moncho-Amor, Javier Crespo, Ander Matheu, Manuel Romero‐Gómez, Benedicto Crespo‐Facorro, Maria Luz Martínez‐Chantar
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.