Pharmacological inhibition of the MST2/Hippo signaling pathway mitigates Toxoplasma gondii-induced apoptosis and immunopathology in macrophage and mice liver.

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that manipulates host cell apoptosis and inflammation to support its survival and replication. Our previous work demonstrated that T. gondii activates the Hippo signaling pathway through phosphorylation of mammalian STE20-like protein kinase 2 (MST2), thereby promoting host cell apoptosis. However, the impact of Hippo pathway inhibition on apoptosis, inflammation, and host protection during infection remains unclear. Here, we demonstrate that T. gondii infection induces apoptosis in RAW264.7 macrophages and causes acute liver injury in mice, accompanied by increased levels of inflammatory cytokines. These changes were associated with decreased total protein levels of MST2, large tumor suppressor homolog 1 (LATS1), and Yes-associated protein (YAP), but increased phosphorylation of these Hippo components. Treatment with XMU-MP-1, a selective MST1/2 inhibitor, alleviated apoptosis, dampened macrophage-mediated excessive inflammation, reduced liver damage and parasite burden, and prolonged survival in acutely infected mice. These findings provide the first direct evidence that pharmacological inhibition of the Hippo signaling pathway mitigates T. gondii-induced apoptosis and immunopathology. Our results highlight the potential of XMU-MP-1 as a host-directed therapeutic strategy. Its efficacy against T. gondii in combination with antiparasitic agents may have remarkable clinical application value.