PXD063321

PXD063321 is an original dataset announced via ProteomeXchange.

Title	Liver-Targeted siRNA Therapy Reveals a Causal Role of Metabolic Dysfunction-Associated Steatotic Liver Disease in Brain Dysfunction
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-09-22
AnnouncementXML	Submission_2025-09-22_06:40:03.180.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mikel Azkargorta
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-25 04:08:34	ID requested
⏵ 1	2025-09-22 06:40:03	announced

Dataset with its publication pending

submitter keyword: hippocampus, social memory, Gal-NAc, sensorimotor processing, neurogenesis,MASLD, dentate gyrus, synapses

Felix Elortza
contact affiliation	Proteomics Platform CIC bioGUNE Bizkaia Tech. Park Build. 800 Derio 48160 Spain
contact email	felortza@cicbiogune.es
lab head
Mikel Azkargorta
contact affiliation	Proteomics Platform CIC bioGUNE
contact email	mazkargorta@cicbiogune.es
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/09/PXD063321

PRIDE project URI

• PRIDE
  1. PXD063321
     1. Label: PRIDE project
     2. Name: Liver-Targeted siRNA Therapy Reveals a Causal Role of Metabolic Dysfunction-Associated Steatotic Liver Disease in Brain Dysfunction