Peer-reviewed veterinary case report
NDRG1 aggravates Sepsis-Induced acute lung injury via PKM2-dependent activation of STAT3 and NF-κB signaling.
- Journal:
- BMC immunology
- Year:
- 2026
- Authors:
- Yang, Yifan et al.
- Affiliation:
- Department of Emergency Medicine · China
- Species:
- rodent
Abstract
BACKGROUND: Sepsis induces systemic inflammation and multi-organ dysfunction, with the lungs frequently affected. Elevated in endothelial cells under hypoxic and inflammatory stressors, NDRG1's contribution to septic pulmonary pathology remains largely uncharacterized. This study investigates whether NDRG1 exacerbates pulmonary inflammation through PKM2-dependent STAT3/NF-κB signaling. METHODS: Mice underwent cecal ligation and perforation to model sepsis, with lung morphology examined by H&E staining. Transcriptional levels of VE-cadherin, ICAM-1, VCAM-1, and cytokines TNF-α, IL-6, and IL-1β were assessed by qPCR, while STAT3/NF-κB phosphorylation was determined by Western blot. NDRG1 localization in pulmonary endothelial cells was evaluated by immunofluorescence, and the NDRG1-PKM2-STAT3/NF-κB axis was further examined using Ndrg1 < sup>-/-</sup> mice and PKM2 modulators (shikonin; TEPP-46). RESULTS: CLP-induced sepsis caused severe pulmonary hemorrhage, edema, and alveolar destruction, accompanied by increased ICAM-1, VCAM-1, and proinflammatory cytokines, as well as reduced VE-cadherin expression. NDRG1 was markedly upregulated in septic endothelia, while its deletion alleviated lung injury, inflammation, and cytokine release by inhibiting PKM2-dependent STAT3/NF-κB phosphorylation. PKM2 inhibition with shikonin reproduced, whereas activation with TEPP-46 abolished, these protective effects, confirming the NDRG1-PKM2-STAT3/NF-κB axis as a pivotal regulator of sepsis-induced pulmonary inflammation. CONCLUSION: By orchestrating downstream STAT3 and NF-κB signaling cascades through PKM2 dependency, NDRG1 contributes to the progression of septic lung injury via increased inflammatory responses and disruption of endothelial integrity. Intervening in this signaling route may offer a viable avenue for therapeutic management of lung injury linked to sepsis.
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Search related cases →Original publication: https://pubmed.ncbi.nlm.nih.gov/41667967/