Experimental and Pharmacoinformatic Studies Reveal Allium cepa L. Extract-Mediated Modulation of Hepatitis B Virus Associated Inflammatory Pathways via Quercetin Glucoside Derivatives

Hepatitis B virus (HBV) infection remains a major global health burden and often progresses to chronic liver inflammation, fibrosis, and hepatocellular carcinoma. Although current antiviral therapies effectively suppress viral replication, their ability to modulate HBV-associated complications remains limited. This study investigates the HBV-associated antiviral and host modulatory potential of methanolic extract of Allium cepa bulb (AC) using integrated in vitro and computational approaches. Cytotoxicity, reverse transcriptase inhibition, time- and dose-dependent inhibition of HBsAg and HBeAg levels, inflammatory cytokines, and specific host gene expression linked to HBV infections were assessed using HBV-expressing HepG2.2.15 cells. LC-MS detected phytocompounds were evaluated for their interaction with TLR4 using molecular docking and dynamics simulations using the Schrödinger suite. AC treatment reduced HBsAg and HBeAg levels up to 61.0% and 75.37%, respectively. Co-treatment with Tenofovir alafenamide enhanced the inhibition to 79.0% and 94.55% without compromising cell viability. Among LC-MS-identified phytocompounds, computational analysis revealed stable interactions with Quercetin 3,4'-diglucoside exhibiting the highest affinity (-14.23 kcal/mol) and maintaining stability with TLR4 throughout a 100 ns simulation. Overall, AC attenuated HBV-induced inflammation through predicted modulation of TLR4-mediated pathways and reduction of HBV antigen secretion, supporting its potential as a complementary therapeutic candidate for the management of chronic HBV infection.