β-elemene directly targets IL-17RA in macrophages to inhibit inflammation and attenuate acute pancreatitis

Acute pancreatitis (AP), a common gastrointestinal emergency, lacks specific treatments. β-elemene (ELE), a sesquiterpene derived from Curcuma phaeocaulis, has attracted attention for its anti-inflammatory and immunomodulatory properties beyond its known antitumor effects. However, its potential protective role in AP and the underlying mechanisms remain incompletely elucidated.

In this study, we investigated the protective effect of ELE against AP and elucidated its potential mechanism of action.

Ceruletide and L-arginine-induced AP mice were used to evaluate the protective effect of ELE on the pancreas of mice. In the mechanism study, RNA sequencing was used to identify potential signaling pathways in pancreatic tissues from AP mice. Subsequently, pull-down, SPR, and DARTS experiments were performed to identify the binding sites between ELE and IL-17RA. Ixekizumab, a clinically available IL‑17RA monoclonal antibody, was used to confirm IL‑17RA as ELE's key target in the AP mouse model.

Our research revealed that ELE effectively alleviated pancreatic damage in AP mice. Pancreatic tissue RNA sequencing revealed a pronounced association with the IL-17 signaling pathway following ELE administration. Further in vivo and in vitro studies revealed that ELE mitigated the inflammatory response in mouse pancreas and bone marrow-derived macrophages by inhibiting the IL-17RA signaling and subsequent NF-κΒ activation. Mechanistically, ELE directly targeted the F534 of the IL-17RA protein. The IL-17RA-neutralizing antibody, ixekizumab, and ELE alleviated AP with comparable efficacy, without a significant difference, suggesting that ELE exerts its protective effects, at least in part, through the IL‑17RA receptor.

Our research revealed that ELE effectively alleviates AP by modulating the IL-17RA-NF-κΒ signaling axis-mediated inflammatory response. These findings suggest that ELE may be a potential therapeutic approach for the anti-inflammatory treatment of AP.