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

Medicinal plants yield bioactive compounds with potential for parasite control. We examined <i>Cynanchi atrati Radix</i> (<i>C. atrati</i>) and its component 4'-hydroxyacetophenone (4'HAP) for activity against <i>Toxoplasma gondii</i> (<i>T. gondii</i>) using cultured cells and mouse infection models. <i>C. atrati</i> extracts limited parasite growth with minimal host-cell toxicity. Chemical screening pinpointed 4'HAP as the active constituent that suppresses <i>T. gondii</i> proliferation <i>in vitro</i> and <i>in vivo</i>. Mechanistically, <i>C. atrati</i> 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.