Therapeutic Targets and Natural Product Screening for Cognitive Impairments Associated with Ferroptosis in Wilson's Disease.

Wang, Xie; Chen, Hong; Zhang, Xiaoyan; Shao, Nan; Chang, Ze; Xie, Daojun; Zhang, Juan

Wilson's disease (WD) is a hereditary condition marked by abnormalities in copper metabolism, which precipitate a spectrum of neurological symptoms and cognitive impairments. Emerging research has highlighted ferroptosis (FPT) as a distinct type of programmed cell death, potentially linked to various cognitive dysfunctions. Nevertheless, the connection between FPT and cognitive impairment in Wilson's disease (WDCI) remains largely enigmatic. In our study, we utilized a multifaceted approach, combining reverse network pharmacology, data mining, and molecular docking techniques to explore the potential for treating WDCI via FPT-related pathways. This thorough analysis revealed a series of proteins, including P38 α , GSK3 β , P53, GPX4, and PTGS2, as pivotal targets for WDCI treatment. Notably, Diosgenin (DG) has been identified as a prospective core component in this therapeutic framework. In the WD copper-loaded rat model, evaluations using the Morris water maze (MWM), Y maze, hematoxylin and eosin staining, transmission electron microscopy (TEM), and immunofluorescence (IF) detection showed that DG significantly enhanced cognitive function recovery, reduced structural damage to hippocampal neurons, and protected mitochondrial integrity. In addition, Western blot (WB) and quantitative reverse transcription PCR (qRT-PCR) analysis showed that DG significantly upregulated the expression levels of proteins and mRNA such as P38 α , GSK3 β , P53, GPX4, and PTGS2 in animal and cell models. Furthermore, DG effectively reversed the dysregulated expression of oxidative stress markers, including Fe 2 , malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS). This study elucidates the neuroprotective effect of DG on hippocampal neurons by activating the P38 α -mediated FPT pathway, highlighting its efficacy as a potent monomer in traditional Chinese medicine and illuminating its potential role in the clinical treatment of WDCI.

COPPER metabolism; STEROID drugs; CHINESE medicine; COMPUTER-assisted molecular modeling; IN vitro studies; PROTEINS; BIOLOGICAL models; SUPEROXIDE dismutase; DATA mining; MITOCHONDRIA; PHARMACEUTICAL chemistry; ELECTRON microscopy; NEURONS; IN vivo studies; FLUORESCENT antibody technique; REVERSE transcriptase polymerase chain reaction; OXIDATIVE stress; DESCRIPTIVE statistics; RATS; MESSENGER RNA; IRON compounds; REACTIVE oxygen species; CELL death; COGNITION disorders; HEPATOLENTICULAR degeneration; ANIMAL experimentation; CONVALESCENCE; WESTERN immunoblotting; ONE-way analysis of variance; BENZOPYRANS; STAINS & staining (Microscopy); HIPPOCAMPUS (Brain); DATA analysis software; CELL survival; BIOMARKERS; MALONDIALDEHYDE

American Journal of Chinese Medicine, 2024, Vol 52, Issue 8, p2423

0192-415X

Academic Journal

10.1142/S0192415X24500927