Moscatilin alleviates severe acute pancreatitis by activating the NRF2/HO-1 pathway to inhibit ferroptosis.

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disease without effective therapeutic interventions. Moscatilin (Mos), a bioactive biphenyl compound derived from Dendrobium, exhibits notable anti-tumor and anti-inflammatory properties; however, its potential application in the treatment of SAP remains unexplored. This study aimed to investigate the protective effects of Mos against SAP and its underlying mechanism. In the caerulein/LPS-induced SAP mouse model and in vitro SAP model, using hematoxylin-eosin (H&E) staining, ELISA and other detection, we demonstrate that Mos significantly attenuated pancreatic injury, decreased serum amylase and lipase levels, and inhibited the production of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. Western blot showed that Mos up-regulated the expression of GPX4 and SLC7A11 and down-regulated ACSL4. Meanwhile, Mos inhibited lipid peroxidation and attenuated ferroptosis as measured by glutathione (GSH), malondialdehyde (MDA) and Fe2+ concentrations. Co-IP assay showed that Mos directly binds KEAP1, disrupting its interaction with NRF2, preventing NRF2 ubiquitination and degradation, and activating the NRF2/HO-1 signaling pathway to exert its protective effect. These beneficial effects were effectively reversed by the use of the NRF2 inhibitor ML385 in rescue experiments. In conclusion, our findings demonstrate that Mos mitigates SAP progression by inhibiting ferroptosis and inflammatory responses via targeting KEAP1, blocking NRF2 degradation, and activating the NRF2/HO-1 pathway. This study provides novel insights into ferroptosis-targeted therapeutic strategies for SAP and offers experimental evidence supporting the use of dendrobium-derived compounds in the treatment of acute pancreatitis.