Therapeutic Potential of Gynostemma pentaphyllum (Thunb.) Makino Against COVID-19 Identified Through Network Pharmacology

<b>Background/Objectives:</b> The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. <i>Gynostemma pentaphyllum</i> (Thunb.) Makino, a traditional herbal medicine rich in flavonoids and saponins, exhibits diverse pharmacological activities, including immunomodulatory and cardiovascular effects. In this study, we investigated the potential of <i>G. pentaphyllum</i> as a complementary treatment for COVID-19 using a network pharmacology approach combined with molecular docking analysis. <b>Methods:</b> To delve into the therapeutic mechanisms of <i>G. pentaphyllum</i>, we identified 59 active compounds and predicted 408 protein targets, of which 19 overlapped with COVID-19-associated genes, including <i>IL1B, IL6, TNF, ACE</i>, and <i>REN</i>. GO and KEGG enrichment analyses were conducted to determine relevant biological processes and pathways, focusing on cytokine signaling, inflammatory responses, and the renin-angiotensin system. Network analyses evaluated interactions of flavonoids and triterpenoid saponins with immunological, inflammatory, renin-angiotensin system, and host entry pathways. Molecular docking was performed to validate the binding affinities of key compounds to their predicted targets. <b>Results:</b> The compound-target-pathway network revealed class-specific patterns: flavonoids primarily mapped to immuno-inflammatory nodes, whereas triterpenoid saponins were enriched for renin-angiotensin system/host-entry-related targets. Docking energies spanned -6.1 to -11.9 kcal/mol, with six compound-target pairs ≤ -10.0 kcal/mol. Notably, NOS2-rutin (-11.9 kcal/mol), NOS2-gypenoside LI (-11.6 kcal/mol), and ACE-gypenoside LI (-11.3 kcal/mol) showed the strongest affinities. <b>Conclusions:</b> These findings provide evidence that <i>G. pentaphyllum</i> exerts therapeutic effects through the complementary actions of flavonoid and saponin components, each modulating distinct molecular pathways. This dual mechanistic potential underscores the value of <i>G. pentaphyllum</i> as a versatile therapeutic for COVID-19 therapy.