<i>Phyllanthus amarus</i> as a Therapeutic Candidate Against Hepatitis E: Network Pharmacology and Molecular Docking Study

ABSTRACT Hepatitis E virus (HEV)‐induced liver infection represent a major global health challenge, causing thousands of deaths annually owing to the lack of effective antiviral therapies. This study explored the therapeutic potential of Phyllanthus amarus against HEV using an integrated network pharmacology approach. Bioactive compounds from P. amarus were selected based on drug‐likeness (≥0.18) and oral bioavailability (≥30%) criteria. Target proteins of these compounds were predicted using SwissTargetPrediction (probability score&gt;0.1) and Similarity Ensemble Approach (SEA) ( p ≤0.05, Z‐score &gt;5, and Tc‐score&gt;0.4) databases, while HEV‐associated genes were sourced from GeneCards (relevance score (RS) &gt; median RS) and DisGeNET. Overlapping targets between the plant and disease were identified as core therapeutic candidates and further analyzed through protein–protein interaction and gene enrichment analysis using the DAVID tool. Network visualization using Cytoscape revealed key interactions among active compounds, target genes, and disease pathways. Eighteen phytochemicals namely β‐Sitosterol, ellagic acid, ethyl linolenate, eucalyptol, furosin, hinokinin, kaempferol, linoleic acid, linolenic acid, melatonin, methyl 9,12‐octadecadienoate, methyl 9‐octadecenoate, methyl linolenate, phyllanthin, phytol, quercetin, ricinoleic acid, and stigmasterol were identified as bioactive components. Among 315 core targets, HSP90AA1, EGFR, and SRC were highlighted as promising antiviral targets. Molecular docking showed strong binding of Ellagic acid, Stigmasterol and Quercetin to these proteins respectively, with molecular dynamics simulations, free energy calculations, and principal component analysis confirming their stability and binding efficacy. While findings suggest P. amarus as a potential anti‐HEV agent, clinical validation is needed to ensure its safety and therapeutic effectiveness.