Emapunil attenuates ulcerative colitis by suppressing Z-DNA binding protein 1 driven pyroptosis and pro-inflammatory polarization in macrophages

BackgroundThe pathogenesis of ulcerative colitis (UC) remains incompletely understood, and effective therapeutic targets are still lacking in clinical practice. Macrophage pyroptosis and polarization imbalance are core events in UC progression.

As a key upstream regulator of pyroptosis, the role of Z-DNA binding protein 1 (ZBP1) in UC-associated macrophages has not been systematically elucidated. Our previous study demonstrated that Emapunil could suppress macrophage inflammation and downregulate ZBP1 expression, suggesting its potential as a candidate agent for UC treatment.MethodsImmunofluorescence was used to detect the expression and localization of ZBP1 in colorectal tissues from UC patients and DSS-induced colitis mice.

ZBP1 overexpression, knockdown, and Emapunil intervention were performed in macrophages to analyze their effects on pyroptosis, polarization, NF-κB pathway, and intestinal barrier function. The therapeutic effect and mechanism of Emapunil on UC were verified via in vitro and in vivo experiments.ResultsZBP1 was significantly upregulated in colorectal macrophages from UC patients.

Overexpression of ZBP1 induced macrophage pyroptosis and M1 polarization, activated the NF-κB pathway and impaired intestinal barrier integrity, whereas ZBP1 knockdown markedly reversed these effects. By targeting TSPO, Emapunil effectively suppressed macrophage pyroptosis and inflammatory polarization via downregulating ZBP1, alleviated DSS−induced colonic injury, and preserved intestinal barrier function in mice.ConclusionZBP1 aggravates intestinal inflammation and barrier damage by driving macrophage pyroptosis and pro-inflammatory polarization, representing a novel key molecule regulating abnormal macrophage activation in UC.

By targeting TSPO, Emapunil exerts anti−UC effects through downregulation of ZBP1, thereby providing a novel mechanism and a potential therapeutic strategy for the clinical management of ulcerative colitis.