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DCK (diquat)-induced lung injury

ABSTRACT: Diquat (DQ) poisoning is a severe medical condition with life-threatening implications and multi-organ dysfunction, yet its underlying mechanism remains incompletely understood. This study unveils a critical process in DQ-induced toxicity. DQ disrupts the mitochondrial genome stability in endothelial cells, leading to the accumulation of Z-form DNA. This triggers an interaction between Z-DNA binding protein 1 (ZBP1) and receptor interacting protein kinase 3 (RIPK3), setting off RIPK3-dependent necroptotic and ferroptotic signaling pathways. Depletion of ZBP1 or RIPK3 in endothelial cells effectively inhibits both necroptosis and ferroptosis, reducing organ damage and mortality. Importantly, we discover that RIPK3 plays a dual role. It phosphorylates MLKL to induce necroptosis and phosphorylates FSP1, inhibiting its enzymatic activity and promoting ferroptosis. The phosphorylation of T163 in FSP1 is crucial for suppressing its activity. Combining the deletion of MLKL with vitamin K treatment proves highly effective in mitigating multi-organ damage and lethality caused by DQ.

ORGANISM(S): Mus musculus

PROVIDER: GSE244858 | GEO | 2024/03/25

REPOSITORIES: GEO

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ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

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2021-04-28 | PXD015537 | Pride

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2022-07-30 | PXD033488 | Pride

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