N-myc and STAT interactor promotes poly(I:C)-induced pulmonary coagulopathy via STAT3-dependent tissue factor

Viral pneumonia-associated coagulopathy is a major determinant of mortality, yet the upstream molecular drivers initiating the coagulation cascade remain incompletely understood.

We integrated bulk and single-cell transcriptomics to map viral infection signatures. Mechanistic and therapeutic evaluations were performed in a poly(I:C)-induced pneumonia model utilizing candidate gene-knockout mice and STAT3 inhibition (Stattic), with endpoints including lung injury, tissue factor (TF) expression, and microthrombosis.

We identified N-myc and STAT interactor (NMI) as a critical damage-associated molecular pattern (DAMP) promoting poly(I:C)-induced pulmonary coagulopathy. Transcriptomic analyses across human and murine viral pneumonia datasets revealed robust NMI upregulation, which strongly correlated with coagulation markers. Mechanistically, extracellular NMI activates alveolar epithelial STAT3 signaling, directly upregulating TF to initiate the extrinsic coagulation cascade. In vivo, Nmi ablation or pharmacological STAT3 inhibition significantly attenuated lung microthrombosis and coagulopathy. Notably, this protective phenotype in Nmi knockout mice was reversed by recombinant NMI administration.

Our findings elucidate the NMI-STAT3-TF axis as a key contributor to pulmonary coagulopathy. Targeting this axis may offer a potential preclinical therapeutic strategy for managing thrombotic complications in virus-induced lung inflammation.