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

作者：Deng LT, Yang H, Zhang XF, Lin ZX, Kuang N, Jiang HY, Liu PZ, Li YG, Li XH, Li WZ, Ni CJ, Qiu MJ, Chao Y, Pan YF, Yang YY, Zhu YT, Zhao Y, Ren JA, Wu XW · 发表于：Military Medical Research · 年份：2026 · DOI：10.1016/j.mmr.2026.100059 · 研究领域：Klebsiella pneumoniae (KP)、Legumain (LGMN)、Macrophage、Sepsis、Signal transducer and activator of transcription 3 (STAT3)、Z-DNA binding protein 1 (ZBP1)

BACKGROUND: 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. METHODS: 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. RESULTS: ZBP1 activation was driven by both type I interferon (IFN-I) signaling and mitochondrial damage. Mechanistically, ZBP1 directly interacted with signal tra...