Investigating the anti-SARS-CoV-2 activity of caffeic acid: A combined network pharmacology and laboratory study

The COVID-19 pandemic necessitated the urgent identification of effective antiviral agents, with natural compounds such as caffeic acid (CA) emerging as candidates based on broad-spectrum antiviral action. While prior computational studies suggested prospective therapeutic activity against SARS-CoV-2, a systematic, integrated study validating CA's multi-target mechanism and functional efficacy was lacking. This study was to explore and validate the molecular targets and antiviral efficacy of caffeic acid against SARS-CoV-2. Network Pharmacology (NP) was employed using GeneCards, DisGeNET, and OMIM to identify multiple inflammation and entry-related targets including ACE2, TNF-á, and NLRP3. PPI analysis revealed a highly connected network, predicting that CA targets the Renin-Angiotensin System (RAS) and key inflammatory mediators. Caffeic acid showed weak antiviral activity against SARS-CoV-2 in vitro, with an IC50 of 278 ìÌ and SI > 1, which indicates weak activity according to antiviral screening standards and pharmacologically low potency. The predicted pathways may indeed be valid targets, but caffeic acid did not specifically affect the mechanisms contributing to the antiviral response. The weak activity measured may be due to non-specific interactions and not the pathways targeted by the predictions.