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

Background/Objectives: The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. Gynostemma pentaphyllum (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 G. pentaphyllum as a complementary treatment for COVID-19 using a network pharmacology approach combined with molecular docking analysis. Methods: To delve into the therapeutic mechanisms of G. pentaphyllum, we identified 59 active compounds and predicted 408 protein targets, of which 19 overlapped with COVID-19-associated genes, including IL1B, IL6, TNF, ACE, and REN. 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. Results: 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. Conclusions: These findings provide evidence that G. pentaphyllum 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 G. pentaphyllum as a versatile therapeutic for COVID-19 therapy.