Abstract
Hepatic encephalopathy (HE) is a central nervous system complication triggered by hyperammonemia, with a complex and not yet fully understood pathogenesis. A1-type astrocytes (AS) are a critical pathological feature of HE, but the specific mechanisms by which ammonia induces AS pathology remain to be elucidated. Previous findings by the applicant have shown that the absence of the RhCG ammonia transporter significantly improves mitochondrial damage and activation phenotype in HE mice, accompanied by an upregulation of the key ferroptosis factor SLC7A11. Combining bioinformatics predictions and literature reports, RhCG may mediate mitochondrial autophagy through PINK1 and synergistically regulate glutamate metabolic reprogramming with SLC7A11. Based on this, the present study proposes that RhCG drives abnormal accumulation of glutamate in AS via the PINK1/SLC7A11 signaling axis, simultaneously inducing lipid peroxidation and oxidative stress associated with ferroptosis, thereby triggering A1-type activation, which collaboratively disrupts the blood-brain barrier and exacerbates neuroinflammation. This project aims to systematically dissect the molecular pathways by which RhCG regulates glutamate metabolic reprogramming and ferroptosis using HE animal models and AS-specific knockout systems, combined with metabolomics and molecular interaction techniques. The research outcomes will provide new theoretical foundations and potential targets for the prevention and treatment of HE, with significant scientific and clinical implications.
