Inhibition of the STAT3-EPHX2 axis promotes regression of ulcerative colitis by treatment with novel porphyrin derivative.

LD4, a novel porphyrin derivative, has attracted much attention for its excellent anti-inflammatory properties. It can promote the healing of colonic mucosa, reduce inflammatory response, regulate oxidative stress, and thus improve ulcerative colitis (UC) symptoms. However, the specific signaling pathways of LD4-PDT involved in UC have not been explored. The present study aimed to elucidate the effects of LD4 on UC and to investigate the underlying mechanisms both in vivo and in vitro. We classified and screened the LD4-PDT proteomic data to obtain key targets. Proteomic data revealed that EPHX2 and STAT3 are key targets of LD4-PDT for UC. Moreover, transcription factor STAT3 positively regulates the expression of EPHX2. Inhibiting EPHX2 can prevent the activation of NF-κB signaling pathway. Next, through pharmacological inhibition experiments, we confirmed that LD4-PDT can reduce intestinal inflammation by inhibiting STAT3-EPHX2 axis. However, by treating normal intestinal epithelial cells and colon cancer cells with TPPU and Stattic, our data confirmed that the STAT3-EPHX2 axis does not exist in colon cancer. In this study, we demonstrated that the transcription factor STAT3 can positively regulate the expression of EPHX2 in normal colon. LD4 can alleviate UC by inhibiting the STAT3-EPHX2 axis, but this axis does not exist in colon cancer. LD4-PDT may become a new and effective method for treating UC.