Network pharmacology-based identification of neuroprotective compounds in Phyllanthus amarus for the management of Alzheimer’s and Parkinson’s comorbidity

Aim: Neurodegenerative diseases, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD), represent a major global health burden due to their progressive nature and lack of disease-modifying therapies. Increasing evidence suggests that these disorders frequently coexist and share overlapping molecular mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and abnormal protein aggregation. Thus, this study aimed to elucidate the neuroprotective mechanistic potential of Phyllanthus amarus in influencing the shared genes in both AD and PD. Methods: This study employed a network pharmacology approach to investigate the neuroprotective potential of P. amarus in the management of AD-PD comorbidity. Bioactive compounds were identified using gas chromatography-mass spectrometry (GC-MS), followed by in silico screening for drug-likeness and pharmacokinetic properties using ADMETlab 3.0 and ProTox-3.0. Target prediction was conducted using SwissTargetPrediction and SuperPred, while disease-associated genes were retrieved from GeneCards. Overlapping targets were analyzed using protein-protein interaction (PPI) networks, with hub genes identified based on topological parameters. Functional enrichment analyses (GO and KEGG) were performed to elucidate underlying biological pathways. Results: A total of 55 compounds were identified, of which a significant proportion demonstrated favorable drug-likeness properties. Sequential Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening narrowed these to a single lead compound, bicyclo[3.3.1]non-6-en-3-ol, which exhibited acceptable absorption, distribution, metabolism, excretion, and toxicity profiles. Network analysis revealed 137 shared targets between AD and PD, with key hub genes including STAT3, PPARG, HSP90AB1, and HIF1A, etc. indicating their central roles in disease progression. Enrichment analyses highlighted critical pathways related to inflammation, oxidative stress, and signal transduction, including insulin resistance, sphingolipid, and calcium signaling pathways, among others. Conclusions: These findings suggest that P. amarus may exert neuroprotective effects through a multi-target mechanism, supporting its potential as a therapeutic candidate for AD-PD comorbidity. However, experimental validation is required to confirm these in silico predictions and facilitate clinical translation.