MiR-4332 modulates oxidative stress, inflammasome activation through notch1 signaling during Toxoplasma gondii infection.

Toxoplasma gondii manipulates host cell pathways through complex strategies. Oxidative stress and inflammasome activation are key to its pathogenesis, yet the mechanisms by which the parasite triggers these processes to cause host damage remain unclear. In this study, we revealed that T. gondii drives an oxidative stress-inflammation cascade culminating in cellular apoptosis. Specifically, T. gondii infection triggered increased ROS production and disrupted redox homeostasis in host cells, accompanied by protective activation of the Nrf2/Ho-1 antioxidant signaling pathway, NLRP3 inflammasome activation, and significantly elevated apoptosis rates. Mechanistically, this study first demonstrates that T. gondii induces marked downregulation of miR-4332, which activates the Notch1 signaling pathway. This activation mediates transcriptional responses associated with oxidative stress, inflammasome activation, and apoptosis through nuclear effectors. miRNA gain- and loss-of-function experiments established Notch1 signaling as being under miR-4332-dependent regulation, confirming the pleiotropic regulatory properties of miR-4332 in the oxidative stress-inflammation-apoptosis cascade. Functional rescue experiments showed that Notch1 inhibitors significantly reversed T. gondii-induced pathological cascades. This study reveals that T. gondii manipulates the host antioxidant defense via the miR-4332/Notch1 axis, promoting oxidative stress and inflammation. These findings offer new insights into parasite-induced pathology and host adaptation.