Acute lung injury (ALI), which poses a significant public health threat, is commonly caused by sepsis. ALI is associated with permeability and glycolysis changes in pulmonary microvascular endothelial cells. Our study demonstrates that heparin-binding protein (HBP), released from neutrophils during sepsis, exacerbates endothelial permeability and glycolysis, thereby triggering ALI. Through coimmunoprecipitation and mass spectrometry, TRIM21 was identified as a HBP interaction partner. Notably, HBP enhances the protein stability of TRIM21 by inhibiting K48 ubiquitination. TRIM21 binds to and promotes K63-linked ubiquitination of P65, facilitating its nuclear translocation. TRIM21 regulates HPMEC permeability and glycolysis in a manner dependent on P65 nuclear translocation. HBP stabilizes TRIM21 and enhances TRIM21 interactions with P65. Rescue experiments conducted in vivo and in vitro demonstrate that modulation of endothelial permeability and glycolysis by HBP is predominantly mediated through the TRIM21-P65 axis. Our results suggest that targeting the HBP/TRIM21/P65 axis is a novel therapeutic strategy to ameliorate ALI.
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| http://dx.doi.org/10.1007/s10565-025-10005-x | DOI Listing |
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