Abstract: OBJECTIVE To observe the protective effect of glycyrrhizin(GL) on intestinal epithelial cells(IECs) from the perspective of protein kinase R-like endoplasmic reticulum kinase(PERK)-eukaryotic initiation factor 2α(eIF2α)-nuclear factor kappa B(NF-κB) signaling pathway, and to explore the possible therapeutic mechanism of GL on treating ulcerative colitis(UC). METHODS Mice's IECs were cultured and identified by immunofluorescence assay in vitro, endoplasmic reticulum stress model was established by H₂O₂ stimulation, and GL groups were given different doses of GL intervention simultaneously while modeling. The cell's survival rate was assessed by CCK8 method. The apoptosis rate was tested by flow cytometry. The cell barrier permeability was determined by transepithelial resistance and fluorescein isothiocyanate-dextran(FITC-dextran) method. And the proteins' expression levels of PERK-eIF2α-NF-κB pathway were detected by Western blotting. RESULTS Compared with model control group, the survival rates of GL middle and high dose groups were increased(P<0.05 or P<0.01), their apoptosis rates were decreased(P<0.05 or P<0.01). The transepithelial resistance values in GL groups were all distinctly elevated(P<0.01), their FITC-dextran concentration were all markedly declined(P<0.01), and their expression levels of p-PERK, p-eIF2α and NF-κB were all descended(P<0.05 or P<0.01). CONCLUSION GL can increase the survival rate and reduce the apoptosis rate of IECs in vitro under endoplasmic reticulum stress state in mice, and improve the permeability of cell barrier by inhibiting the activation of PERK- eIF2α-NF-κB signaling pathway, which might be partial mechanism of GL protecting IECs and treating UC.