Prediction of Quercetin as a Potential Modulator of HTNV-Related Host Responses: An Integrated Computational Study with Baseline Pharmacological Characterization

Hantaan virus (HTNV) is a rodent-borne zoonotic pathogen that is mainly distributed in East Asia. It is a typical example of a One Health challenge, because it persists in rodent reservoirs without causing disease in the animals but causes severe hemorrhagic fever with renal syndrome (HFRS) when it infects humans. This study employed an integrated bioinformatics approach to systematically identify early-stage HTNV-related host interaction factors, screen potential natural compounds, and predict their underlying therapeutic mechanisms. Integrative bioinformatics analysis identified CXCL10, STAT1, and IL10 as the principal upregulated core genes associated with early-stage HTNV infection. Based on these targets, six candidate natural compounds were retrieved from the HERB database. Notably, quercetin emerged as the most promising candidate, exhibiting a favorable pharmacological profile characterized by high predicted gastrointestinal absorption and an acceptable predicted toxicity profile based on in silico ADMET assessment. Functional enrichment of HTNV-related host interaction targets suggested that HTNV infection may affect multiple host pathways, including HIF-1 signaling. Network pharmacology studies suggest that quercetin may inhibit the damage caused by HTNV infection in the host by regulating the host interaction genes and related pathways associated with HTNV. Combined transcriptomic and database analyses further suggested that quercetin may modulate apoptosis through targets including AKT1, BCL2, and STAT3. In baseline pharmacological assays in uninfected HEK293T cells, quercetin showed low cytotoxicity between 3.90625 and 7.8125 μM, increased cell viability, and reduced transcription of BCL2, MAPK3, and TNF. Molecular docking predicted favorable binding poses of quercetin within HTNV RNA-dependent RNA polymerase (RdRp), with Lys884 and Arg892 as predicted contact residues. In conclusion, these findings identify quercetin as a hypothesis-generating computational candidate for modulating HTNV-related host responses, pending experimental validation. This research framework can provide mechanistic hypotheses regarding host–pathogen interactions and potential intervention targets, thereby supporting the prevention and control of HTNV within the “One Health” framework.