Synergistic Anti-Zika Activity of Repurposed Statin and Clofibrate Combinations: Evidence from Oleic Acid-Mediated Metabolic Complementation

Zika virus (ZIKV) substantially relies on host lipid metabolism, presenting a prime target for host-directed antivirals. To identify host-directed antiviral interventions while circumventing interferon-mediated transcriptomic masking, we curated a dual-virus (dengue and ZIKV) gene signature to query the Connectivity Map. Top lipid-lowering candidates were validated using a reporter virus (rZIKV-Venus) and an authentic wild-type (WT) ZIKV in Vero E6 cells—a model deliberately selected for its interferon deficiency to isolate pure metabolic responses. Dose–response screening of 67 prioritized compounds identified atorvastatin, rosuvastatin, and clofibrate as potent ZIKV inhibitors. Statin–clofibrate combinations exhibited strong synergy, with fractional inhibitory concentration index (FICI) values of 0.203 (atorvastatin–clofibrate) and 0.117 (rosuvastatin–clofibrate) for the 4:1 clofibrate-to-statin ratio and an optimized selectivity index. Mechanistically, exogenous oleic acid supplementation induced significant metabolic complementation, significantly restoring both host lipid droplet (LD) abundance and ZIKV replication readouts suppressed by the dual treatment. Relative LD intensity strongly correlated with viral intensity in both models (Pearson r = 0.951 and 0.956, respectively; both p < 0.0001). These findings demonstrate that concurrent pharmacological modulation of host lipid metabolism exerts synergistic anti-ZIKV effects, highlighting highly curated transcriptomic repurposing as a mechanistic prioritization strategy for host-directed antiviral discovery.