Metabolic dysfunction–associated steatotic liver disease alters brain function and behavior: Insights from liver-targeted siRNA therapy
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.
Authors
- Clàudia Gil‐Pitarch (ORCID: https://orcid.org/0000-0003-2220-0612)
- Verónica Moncho-Amor (ORCID: https://orcid.org/0000-0001-7914-6683)
- Ander Matheu (ORCID: https://orcid.org/0000-0002-1848-0781)
- Ana C. Sánchez-Hidalgo (ORCID: https://orcid.org/0000-0003-4959-4826)
- Rubén Nogueiras (ORCID: https://orcid.org/0000-0002-9976-9930)
- Javier Crespo (ORCID: https://orcid.org/0000-0001-8248-0172)
- Benedicto Crespo‐Facorro (ORCID: https://orcid.org/0000-0003-0033-7132)
- Naroa Goikoetxea‐Usandizaga (ORCID: https://orcid.org/0000-0003-4569-028X)
- Celia Martín-Cuevas (ORCID: https://orcid.org/0000-0003-1074-3724)
- Irene González‐Recio (ORCID: https://orcid.org/0000-0003-1432-8974)
- Víctor Darío Ramos‐Herrero (ORCID: https://orcid.org/0000-0002-6082-7320)
- Manuel Romero‐Gómez (ORCID: https://orcid.org/0000-0001-8494-8947)
- Carolina Conter (ORCID: https://orcid.org/0000-0002-5999-8667)
- Félix Elortza (ORCID: https://orcid.org/0000-0001-8839-5438)
- Claudia M. Rejano-Gordillo (ORCID: https://orcid.org/0000-0003-4586-5975)
- Jon Landa (ORCID: https://orcid.org/0000-0002-7644-7517)
- Maria Luz Martínez‐Chantar (ORCID: https://orcid.org/0000-0002-6446-9911)
- Teresa C. Delgado (ORCID: https://orcid.org/0000-0001-9204-581X)
- Mikel Azkargorta (ORCID: https://orcid.org/0000-0001-9115-3202)
- Antonio Gil‐Gómez (ORCID: https://orcid.org/0000-0001-9622-1761)
- Jon Ander Barrenechea-Barrenechea (ORCID: https://orcid.org/0009-0007-5972-6796)
- L. Estefanía Zapata-Pavas
- Luis Alfonso Martínez‐Cruz (ORCID: https://orcid.org/0000-0002-5856-9377)
- Rocío Gallego Durán
Institutions
- Ikerbasque (ES)
- Universidad de Cantabria (ES)
- BioCruces Health research Institute (ES)
- Biogipuzkoa Health Research Institute (ES)
- Spanish Clinical Research Network (ES)
- CIC bioGUNE (ES)
- Instituto de Investigación Marqués de Valdecilla (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Instituto de Biomedicina de Sevilla (ES)
- Onkologikoa (ES)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES)
- Hospital Universitario Virgen del Rocío (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- Medical Research Network (US)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1126/sciadv.ady9758
- Citations
- 2
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 2.24