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

ABSTRACT

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.