Key result
DPEP1 knockdown reduces LPS-induced endothelial dysfunction and inflammation via the EGR1/NF-κB signaling axis.
Why the study?
Sepsis is characterized by endothelial dysfunction, but the role of Dipeptidase-1 in endothelial dysfunction remains unclear.
DPEP1 contributes to sepsis-associated endothelial dysfunction by promoting NF-κB activation in an EGR1-dependent manner, highlighting a potential therapeutic target for sepsis.
DPEP1 inhibition may reduce sepsis-related endothelial injury in vitro; leaves open whether targeting this axis improves clinical outcomes.
Background: Sepsis is characterized by endothelial dysfunction that contributes to vascular leakage, inflammation, and organ failure. Although metabolic enzymes are increasingly being recognized as regulators of inflammatory signaling, the role of Dipeptidase-1 (DPEP1) in endothelial dysfunction remains unclear. Methods: EA.hy926 cells were exposed to serum from 10 patients with septic shock and 6 healthy controls, while LPS treatment was used to establish an in vitro model of sepsis-associated endothelial injury. DPEP1 expression was assessed by qRT-PCR and Western blotting. Gain- and loss-of-function approaches were used to evaluate the effects of DPEP1 on cell viability, apoptosis, permeability, angiogenic capacity, and production of inflammatory cytokines. Transcriptomic analysis was performed to identify downstream regulators and signaling pathways, followed by validation using immunofluorescence and Western blotting. Results: DPEP1 expression increased in EA.hy926 cells under septic conditions. Overexpression of DPEP1 reduced cell viability, increased apoptosis and permeability, impaired tube formation, and enhanced the production of inflammatory cytokines, whereas DPEP1 knockdown had the opposite effects. Transcriptomic analysis revealed the enrichment of genes involved in transcriptional regulation and inflammatory signaling. Among these, EGR1 expression was reduced following DPEP1 knockdown. Functional experiments showed that DPEP1 modulated the nuclear translocation of NF-κB p65 and phosphorylation of IκBα, while restoration of EGR1 partially rescued NF-κB activation. Conclusion: DPEP1 contributes to endothelial dysfunction under septic conditions and is associated with enhanced inflammatory response. These findings suggest that DPEP1 may promote NF-κB activation in an EGR1-dependent manner, thereby enhancing inflammatory signaling in endothelial cells.
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Lin et al. (2026) studied Sepsis-associated endothelial dysfunction (n=16). DPEP1 overexpression and knockdown vs. Negative control (shRNA_NC or empty vector) was evaluated on Endothelial cell viability, apoptosis, permeability, and inflammatory cytokine production. DPEP1 overexpression aggravated LPS-induced endothelial dysfunction and inflammation, while DPEP1 knockdown attenuated these effects via the EGR1/NF-κB signaling axis.
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