Polydatin protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation

Ulcerative colitis (UC), a form of inflammatory bowel disease, is characterized by a Q7 recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis. Our findings demonstrated that PD mitigated the DSS-induced increases in proinflammatory cytokines (IL-6, TNF-α, and IL-1β), alleviated colon length shortening, reduced morphological damage to the intestinal mucosa, and preserved tight junction proteins (TJ) occludin and Zonula occludens-1 (ZO-1) in both Caco-2 cells and murine models of colitis. Results from bulk RNA sequencing and differential gene analysis suggested a potential role for ferroptosis in the protective mechanisms of PD against UC. Further investigations revealed that PD modulated the expression levels of several ferroptosis-related proteins and transcription factors within the DSS-induced colitis model. Notably, treatment with PD enhanced nuclear translocation of Nrf2, which inhibits ferroptosis while ameliorating oxidative stress through upregulation of Slc7a11 and Gpx4 expression. Additionally, erastin—a known inducer of ferroptosis—reversed the protective effects conferred by PD in the DSS-induced colitis model by downregulating Slc7a11 expression. These findings underscore that PD protects against DSS-induced ulcerative colitis via the Nrf2/ Slc7a11/Gpx4 signaling axis, highlighting its potential as a novel therapeutic agent for UC. The subsequent groups were tested: (1) Control group: the standard incubator became the place where the cells were preserved; (2) DSS group: the cells were treated with 3%DSS at 37°C for 8 h; (3) DSS + PD group: 30 μM PD pre-treatment for 2 h, followed by coprocessing with 3% DSS for 8 h; (4) DSS + PD + Erastin group: with pretreatment, the cells were treated with 5 μM erastin at 37°C for 3 h prior to DSS + PD treatment; (5) DSS + Fer-1 group: the cells were treated with 10 μM Fer-1 at 37°C for 2 h before the DSS treatment. The application of inducers (erastin) and inhibitors (Fer-1) is crucial in the study of ferroptosis and related diseases (Du and Guo, 2022).