ZBP1 activated by mitochondrial damage binds to STAT3 to suppress Legumain production and exacerbate macrophage inflammation in Klebsiella pneumoniae-induced sepsis.

Authors

Li-Ting Deng, Huan Yang, Xu-Fei Zhang, Ze-Xing Lin, Ni Kuang, Hai-Yang Jiang, Pei-Zhao Liu, Yang-Guang Li, Xuan-Heng Li, Wei-Zhen Li, Chu-Jun Ni, Ming-Jie Qiu, Yue Chao, Yu-Fei Pan, Yi-Yu Yang, Ye-Ting Zhu, Yun Zhao, Jian-An Ren, Xiu-Wen Wu

Published in

Military Medical Research. Volume 13. Issue 1. Pages 100059. Epub Jul 30, 2026.

Abstract

Severe bacterial sepsis caused by Klebsiella pneumoniae (KP) is characterized by dysregulated inflammation, multiorgan injury, and high mortality, yet the key molecular drivers of this process remain incompletely understood. This study aimed to elucidate how the Z-DNA binding protein 1 (ZBP1) regulates inflammatory injury during KP-induced sepsis and to identify potential therapeutic targets with translational relevance.
To investigate the role of macrophage ZBP1 in sepsis, we combined transcriptomic datasets from human sepsis cohorts and murine sepsis and KP-infection models with single-cell RNA sequencing of infected tissues. We further established both global and myeloid-specific Zbp1 knockout (Zbp1 ^fl/fl Lyz2-Cre ^+/- ) mice, as well as myeloid-specific Lgmn (encoded Legumain) knockout (Lgmn ^fl/fl Lyz2-Cre ^+/- , Lgmn ^CKO ) mice, to delineate the macrophage-dependent mechanisms of immune regulation. In addition, macrophage-targeted adeno-associated virus 9 (AAV9) vectors driven by the F4/80 promoter were used to overexpress Lgmn in vivo. Flow cytometry, immunofluorescence, and survival analyses were performed to evaluate systemic inflammation, organ injury, and sepsis severity. The effect of recombinant LGMN supplementation on macrophage activation and barrier restoration was also assessed.
ZBP1 activation was driven by both type I interferon (IFN-I) signaling and mitochondrial damage. Mechanistically, ZBP1 directly interacted with signal transducer and activator of transcription 3 (STAT3), suppressed its phosphorylation and nuclear translocation, and consequently inhibited transcription of Lgmn, a gene associated with anti-inflammatory macrophage polarization and tissue repair. Genetic and myeloid-specific deletion of Zbp1 resulted in reduced proinflammatory cytokine production and improved survival in both KP- and cecal ligation and puncture (CLP)-induced sepsis models. In contrast, Lgmn ^CKO aggravated systemic inflammation, organ injury, and barrier dysfunction, whereas macrophage-targeted AAV9-mediated Lgmn overexpression or recombinant LGMN supplementation alleviated macrophage inflammation, restored epithelial function, and improved survival.
These findings reveal a previously unrecognized ZBP1-STAT3-LGMN signaling axis that contributes to immune and inflammatory dysregulation in KP-induced sepsis and suggest that targeting ZBP1 or restoring LGMN activity may represent a promising therapeutic strategy for severe bacterial infections.

PMID:
42571453
Bibliographic data and abstract were imported from PubMed on 09 Aug 2026.

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