Sirt2 inhibitors protect chronic inflammatory disease by improving gut epithelial barrier integrity

Inflammatory Bowel Disease (IBD), as a chronic inflammatory disease, triggers a global health threat with poorly understood mechanisms driving its progression. Unraveling these mechanisms and identifying new therapeutic targets are crucial for improved treatments. Prior studies revealed conflicting roles of Sirtuin 2 (Sirt2) in IBD: genetic knockout of Sirt2 exacerbates IBD, while pharmacological inhibition diminishes its severity. This contradiction hinders Sirt2 inhibitor development for IBD treatment. Our investigation using distinct Sirt2 inhibitors (TM and AGK2), a PROTAC Sirt2 degrader, and genetic knockout mice addressed this puzzle. Both TM and AGK2 showed protective effects in an IBD model induced by DSS, excluding off-target effects. Mechanistically, these inhibitors suppressed ARF6-mediated E-cadherin endocytosis, fortifying intestinal epithelial integrity and the gut barrier, protecting against IBD. Interestingly, the PROTAC Sirt2 degrader, similar to Sirt2 genetic knockout, didn’t offer protection in IBD. This discrepancy suggests that Sirt2 small molecular inhibitors only partially but not all hinder Sirt2's activities, stressing the need for substrate-dependent inhibitors in IBD treatment. Overall, our study provided an interesting example that genetic knockout and pharmacological inhibition were not consistent, and this mechanistic understanding further support Sirt2 as a promising target for treating IBD.