Serum metabolomics identifies GPC depletion in hepatic encephalopathy and its therapeutic potential for cognitive impairment

Background Hepatic encephalopathy (HE), a common neurological complication in end-stage cirrhosis, is a complex disorder whose molecular pathogenesis has yet to be fully elucidated. Metabolomics studies provide novel insights into elucidating the pathological mechanisms of HE. This study aims to screen serum differential metabolites in cirrhosis and HE patients using metabolomics technology, with particular focus on validating the therapeutic effects of key metabolites on HE-associated cognitive dysfunction and its underlying mechanisms. Methods This study was designed to first enroll 20–30 subjects per group (including healthy controls, cirrhosis patients, and HE patients) for serum untargeted metabolomic analysis using liquid chromatography-tandem mass spectrometry technology, combined with multivariate statistical analysis and pathway enrichment methods to identify key metabolites. This study established five experimental rat groups and developed a HE rat model via modified common bile duct ligation to evaluate the effects of key metabolite supplementation on cognitive function, while simultaneously assessing therapeutic outcomes through histopathological examination and ultrastructural observations. Results A total of 2,375 metabolites were identified by metabolomic analysis. Comprehensive analysis screened five differentially expressed metabolites (including sn-glycero-3-phosphocholine (GPC)) significantly associated with disease progression, with GPC prioritized for subsequent validation of its effects on cognitive function in HE. The results demonstrated that GPC supplementation notably improved HE rats’ spatial working memory and motor ability, while alleviating hepatic inflammatory infiltration and blood-brain barrier damage. Conclusion This study is the first to discover and confirm the protective effect of GPC in improving cognitive dysfunction in HE, and the mechanism may be related to preserving the integrity of the blood-brain barrier.