Crocetin curbs radiation induced intestinal injury by blocking KAT2A/NLRP3 succinylation

Irradiation (IR) is known to damage the intestinal mucosal barrier, leading to serious intestinal injury. Crocetin is a natural active compound derived from the enzymatic deglycosylation of crocin in the intestines. The role of crocetin and its underlying molecular mechanism in IR-induced intestinal injury have not yet been reported. Here, we investigated the role of crocetin in protecting against IR-induced intestinal injury and explored its downstream molecular mechanisms. First, we established an in vivo animal model and performed histological analyses. The results indicated that crocetin ameliorated IR-induced intestinal injury. Functionally, crocetin treatment enhanced the viability of intestinal cells subjected to IR while suppressing pyroptosis. Succinylation is a post-translational modification regulating various cellular functions. Here, we found that the mRNA and protein levels of the succinylation regulator, lysine acetyltransferase 2A (KAT2A), were decreased in both in vitro and in vivo models following crocetin treatment. Further investigation revealed that KAT2A stabilizes the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) protein by promoting the succinylation of NLRP3 at the K21 site. Finally, rescue assays indicated that overexpression of NLRP3 attenuated the effects of KAT2A silencing on the viability and pyroptosis in IR-induced HIECs. Collectively, our study demonstrates that crocetin protects against IR-induced intestinal injury by suppressing KAT2A-mediated succinylation.