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

## TL;DR

A plant extract and its compound inhibit parasite growth by targeting a specific host signaling pathway.

## Contribution

Identifies a plant-derived compound and its mechanism of action against Toxoplasma gondii via the GSK3β/HIF-1α pathway.

## Key findings

- C. atrati and 4′HAP suppress T. gondii proliferation in vitro and in vivo.
- 4′HAP activates GSK3β and destabilizes HIF-1α, reducing parasite fitness.
- Pharmacologic GSK3β inhibition reverses anti-parasitic effects, confirming pathway involvement.

## Abstract

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.

•C. atrati and its bioactive compound 4′HAP can suppress T. gondii proliferation•C. atrati and 4′HAP inhibit host GSK3β/HIF-1α signaling by reducing HIF-1α stability•GSK3β activation is essential for the anti-parasitic effects of C. atrati and 4′HAP•C. atrati or 4′HAP are promising anti-parasitic candidates for ocular toxoplasmosis

C. atrati and its bioactive compound 4′HAP can suppress T. gondii proliferation

C. atrati and 4′HAP inhibit host GSK3β/HIF-1α signaling by reducing HIF-1α stability

GSK3β activation is essential for the anti-parasitic effects of C. atrati and 4′HAP

C. atrati or 4′HAP are promising anti-parasitic candidates for ocular toxoplasmosis

Parasitology; microbial metabolism; microbiology parasite