GSK3β/HIF-1α signaling-dependent anti-parasite effect of Cynanchi atrati Radix

Medicinal plants yield bioactive compounds with potential for parasite control. We examined Cynanchi atrati Radix (C. atrati) and its component 4'-hydroxyacetophenone (4'HAP) for activity against Toxoplasma gondii (T. gondii) using cultured cells and mouse infection models. C. atrati extracts limited parasite growth with minimal host-cell toxicity. Chemical screening pinpointed 4'HAP as the active constituent that suppresses T. gondii proliferation in vitro and in vivo. Mechanistically, C. atrati and 4'HAP activated GSK3β, destabilized HIF-1α, and curtailed parasite fitness; pharmacologic GSK3β inhibition restored parasite growth, whereas HIF-1α depletion further reduced survival, highlighting the GSK3β/HIF-1α axis as a host pathway that constrains infection. These results identify a plant-derived small molecule and its mechanistic target for host-directed antiparasitic therapy and provide a framework for developing treatments for toxoplasmosis.