Sestrin2 improves intestinal ischemia-reperfusion injury through the TFEB-mediated autophagy/lysosomal pathway.

Sestrin2 is a stress-inducible protein that exhibits protective effects against ischemia-reperfusion injury in various organs. However, the specific roles and mechanisms of Sestrin2 in intestinal ischemia-reperfusion (IIR) injury have yet to be fully elucidated. The present study aims to investigate the role of Sestrin2 in intestinal IIR injury and its underlying mechanisms. We found that in the IIR model of C57BL/6 J mice, Sestrin2 expression increased following IIR injury, accompanied by enhanced lysosomal activity and autophagy activation. Further cellular experiments demonstrated that overexpression of Sestrin2 increased autophagic flux, enhanced lysosomal activity, and mitigated cellular injury. These effects were abrogated by Sestrin2 knockdown. Additionally, we discovered that Sestrin2 interacts with transcription factor EB (TFEB), and that knockdown of Sestrin2 resulted in decreased nuclear translocation of TFEB, leading to a reduction in autophagic flux due to impaired lysosomal function. The TFEB activator (TFEB A1) promoted TFEB nuclear translocation and reversed autophagy/lysosomal pathway (ALP) dysfunction and cellular damage caused by Sestrin2 knockdown. In conclusion, Sestrin2 protects against IIR injury by promoting TFEB nuclear translocation, enhancing lysosomal activity, accelerating autophagosome turnover and substrate degradation, and increasing autophagic flux. These findings provide novel insights and potential targets for the treatment of IIR injury.