Isorhamnetin alleviates ferroptosis-mediated colitis by activating the NRF2/HO-1 pathway and chelating iron.

ABSTRACT

Ferroptosis of intestinal epithelial cells (IECs) had been identified as a key factor in the development of ulcerative colitis (UC). Therefore, targeted inhibition of ferroptosis may provide a new strategy for the treatment of UC. Isorhamnetin (ISO) was an O-methylated flavonol with therapeutic effects on a variety of diseases, such as cardiovascular disease, neurological disorders and tumors. However, the role and mechanism of ISO in ferroptosis and associated colitis were rarely investigated. In this study, we demonstrated that ISO could effectively alleviate intestinal inflammation by inhibiting ferroptosis of IECs in DSS-induced mice. Moreover, our results shown that ISO acted as a potent and common ferroptosis inhibitor in multiple human and murine cell lines. Mechanistically, ISO inhibited ferroptosis independent of its previously reported targets MEK1 and PI3K, but alleviated oxidative stress by targeting and activating NRF2. Furthermore, ISO could also directly chelate iron to hinder ferroptosis. In conclusion, our study indicated that ISO as a novel potential ferroptosis inhibitor, providing a promising therapeutic strategy for ferroptosis-related colitis.