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Liver-Targeted siRNA Therapy Reveals a Causal Role of Metabolic Dysfunction-Associated Steatotic Liver Disease in Brain Dysfunction

ABSTRACT: Metabolic-dysfunction-associated steatotic liver disease (MASLD) has traditionally been studied as a liver-centric condition. However, growing clinical and experimental evidence reveals a strong link between MASLD and cognitive impairment and sensorimotor alterations. The mechanisms underlying this liver-brain axis remain poorly defined, and whether hepatic dysfunction alone is sufficient to drive central nervous system deficits is unclear. Using diet-induced non-obese mouse models of MASLD, we performed comprehensive neurocognitive and behavioral assessments. MASLD was associated with marked alterations in social memory, sensorimotor processing, and hippocampal function, including decreased parvalbumin-positive interneurons, reduced dendritic spine density, and diminished indicators of neurogenesis in the hippocampal dentate gyrus. Then, we selectively modulated liver metabolism through a hepatocyte-targeted siRNA therapy against Cyclin M4 (CNNM4), a magnesium transporter dysregulated in MASLD, employing GalNAc-siRNA technology for targeted delivery. Notably, liver-specific intervention with siRNA-CNNM4 reversed features of impaired social memory and sensorimotor processing through 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. Importantly, hepatic-specific intervention restores brain function, strongly supporting the existence of a causal and therapeutically targetable liver-brain axis. These results open new avenues for treating MASLD-associated neurological complications through liver-directed therapies.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Dentate Gyrus

DISEASE(S): Metabolic Dysfunction-associated Steatotic Liver Disease

SUBMITTER: Mikel Azkargorta

LAB HEAD: Felix Elortza

PROVIDER: PXD063321 | Pride | 2025-09-22

REPOSITORIES: Pride

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			Action	DRS
	221117_221006B_Claudia_11_S1-B11_1_6162.d.rar	Other
	221117_221006B_Claudia_12_S1-B12_1_6163.d.rar	Other
	221117_221006B_Claudia_16_S1-C1_1_6164.d.rar	Other
	221117_221006B_Claudia_17_S1-C2_1_6165.d.rar	Other
	221117_221006B_Claudia_1_S1-B7_1_6158.d.rar	Other

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Project description:Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathophysiological mechanisms remain elusive. It is a progressive disease, encompassing hepatic steatosis, steatohepatitis with(out) fibrosis and ultimately cirrhosis and hepatocellular carcinoma. DNA methylation (DNAm) is dysregulated in MASLD and may underpin key pathogenic mechanisms. Additionally, aging is associated with MASLD and shares common processes of chronic inflammation and oxidative stress. Therefore, this study focuses on DNAm changes in relation to MASLD progression and epigenetic age acceleration (EAA). Results: Liver biopsies from 22 MASLD patients were analyzed using Infinium MethylationEPIC BeadChip arrays. Strikingly, progression of MASLD was characterized by gradual DNAm changes, revealing associated KEGG pathways. Additionally, Horvath’s EAA significantly correlated with MASLD stage and individual histological MASLD parameters while LiverClock’s EAA correlated only with MASLD stage. In contrast, both Horvath’s intrinsic EAA and HepClock’s EAA showed no significant correlations. Integrative analyses, leveraging both gradual MASLD and Horvath’s EAA DNAm signatures, gene expression (n = 118), and a MASLD-specific transcriptional regulatory network, identified (regulon-specific) transcription factors implicated in MASLD and EAA progression, representing a transcription factor-network of redox (ferroptosis), immune, and metabolic/endocrine related epigenetic processes. Conclusion: Gradual DNAm changes were found to align with progression of MASLD and EAA, with EAA a potential non-biased quantitative biomarker for MASLD. Integrative analysis highlighted potential new therapeutic transcription factor targets, with special emphasis on AEBP1 and emerging nuclear receptors including CAR(NR1I3), MR(NR3C2), GR(NR3C1), and ESRRG, underscoring the potential of epigenetic redox-metabolic therapies for MASLD

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Liver-Targeted siRNA Therapy Reveals a Causal Role of Metabolic Dysfunction-Associated Steatotic Liver Disease in Brain Dysfunction

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