Metabolic dysfunction-associated steatotic liver disease alters brain function and behavior: Insights from liver-targeted siRNA therapy.

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 <i>N</i>-acetylgalactosamine small interfering RNA (siRNA) therapy against Cyclin M4 (<i>CNNM4</i>), a magnesium transporter dysregulated in MASLD. Liver-specific intervention with siRNA-<i>Cnnm4</i> 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.