Intestinal ischemia/reperfusion (II/R) injury is a common life-threatening complication with high morbidity and mortality. Chebulae Fructus Immaturus, the unripe fruit of Terminalia chebula Retz., also known as “Xiqingguo” or “Tibet Olive” in China, has been widely used in traditional Tibetan medicine throughout history. The phenolic acids’ extract of Chebulae Fructus Immaturus (XQG for short) has exhibited strong antioxidative, anti-inflammation, anti-apoptosis, and antibacterial activities. However, whether XQG can effectively ameliorate II/R injuries remains to be clarified. Our results showed that XQG could effectively alleviate II/R-induced intestinal morphological damage and intestinal barrier injury by decreasing the oxidative stress, inflammatory response, and cell death. Transcriptomic analysis further revealed that the main action mechanism of XQG protecting against II/R injury was involved in activating PPARα and inhibiting the NF-κB-signaling pathway. Our study suggests the potential usage of XQG as a new candidate to alleviate II/R injury.

Background: Intestinal ischemia–reperfusion injury (IIRI) is driven by oxidative stress, excessive inflammation, Endoplasmic Reticulum Stress (ERS), and disruption of the intestinal epithelial barrier. Corilagin, a natural ellagitannin with antioxidant and anti-inflammatory activities, has shown protective effects against IIRI; however, its cross-species and multitarget mechanisms remain unclear. Methods: This study investigated the protective mechanisms of Corilagin against IIRI by integrating Corilagin-related targets, IIRI-associated genes, and an ERS gene set. Differential expression analyses of GSE37013 and GSE96733 were combined with an ensemble machine-learning framework comprising 15 algorithms to prioritize core genes. Molecular docking and 100-ns all-atom molecular dynamics simulations using the AlphaFold-predicted full-length human NRF2 structure were performed to assess the predicted Corilagin-NRF2 interaction. A mouse IIRI model was used to validate selected molecular and histological findings by histology, RT-qPCR, Western blotting, and immunohistochemistry. In IEC-6 cells subjected to OGD/R, NRF2 immunofluorescence and siRNA-mediated knockdown of Nrf2 or Abcg2 were used to further evaluate the involvement of NRF2 and ABCG2 in Corilagin-mediated protection. Results: Intersection analysis identified 472 genes shared among Corilagin-related targets, IIRI-related genes, and ERS-associated genes. Enrichment analysis highlighted stress- and injury-related pathways, including PI3K-Akt signaling. Ensemble machine learning prioritized 12 core genes across human and mouse datasets, with ABCG2, IL10, and PRKCZ emerging as prominent candidates. Docking and 100-ns MD simulations supported persistent Corilagin retention within the predicted NRF2 binding region, while post-relaxation MM/GBSA analysis indicated favorable interaction energetics. In vivo , Corilagin pretreatment reduced inflammation and oxidative stress-related changes, restored apical ABCG2 and tight-junction protein expression, improved mucosal morphology, and altered CHOP expression. In IEC-6 cells, Nrf2 or Abcg2 knockdown weakened Corilagin-mediated preservation of Occludin, Claudin-1, and ZO-1 under OGD/R, supporting NRF2–ABCG2 involvement in this protective response. Conclusion: Corilagin may alleviate IIRI by modulating ERS-related molecular changes and preserving the intestinal epithelial barrier with NRF2 and ABCG2 contributing to a candidate regulatory module involved in this protective response. These findings provide computational and experimental support for further investigation of Corilagin as a potential intervention for IIRI and illustrate the value of combining multi-source data integration with ensemble machine learning to characterize the multitarget pharmacology of natural products.