BECN1 Protects Against Intestinal Ischemia/Reperfusion Injury by Promoting NLRP3 Ubiquitination and Suppressing...

Intestinal ischemia/reperfusion (I/R) injury causes severe inflammation and disruption of the epithelial barrier, often leading to life-threatening complications. Although autophagy is known to provide tissue protection during I/R, the mechanisms linking autophagy to inflammasome regulation remain unclear. This study aimed to investigate the role of Beclin 1 (BECN1) in regulating NLRP3 inflammasome activation during intestinal I/R injury.

Intestinal I/R models were used to examine changes in BECN1 expression in intestinal epithelial cells. Conditional knockout mice lacking Becn1 in intestinal epithelial cells were generated to evaluate its functional role in vivo. Autophagic flux, NLRP3 ubiquitination, inflammasome activation, and inflammatory cytokine production were assessed using molecular and biochemical approaches. In addition, the therapeutic potential of a cell-penetratingTAT-BECN1 peptide was evaluated in the I/R model.

BECN1 expression was significantly upregulated in intestinal epithelial cells following I/R injury. Mechanistically, BECN1 promoted ubiquitin-dependent degradation of NLRP3, thereby limiting inflammasome activation. Conditional deletion of Becn1 in intestinal epithelial cells exacerbated intestinal injury and increased inflammatory cytokine production. Conversely, administration of the TAT-BECN1 peptide restored autophagic flux, enhanced NLRP3 ubiquitination, and attenuated epithelial damage and inflammation after I/R.

BECN1 protects against intestinal I/R injury by promoting NLRP3 ubiquitination and suppressing inflammasome activation through the autophagy pathway. These findings reveal a previously unrecognized mechanism linking autophagy to inflammasome regulation and suggest that targeting the BECN1-autophagy axis may represent a promising therapeutic strategy for intestinal I/R injury.