# Danthron Attenuates Intestinal Inflammation by Modulating Oxidative Stress via the EGFR-PI3K-AKT and Nrf2-HO-1 Pathways

## TL;DR

Danthron, a compound from rhubarb, reduces intestinal inflammation by targeting key pathways involved in oxidative stress and inflammation, showing potential as a treatment for inflammatory bowel disease.

## Contribution

Danthron's novel dual modulation of EGFR-PI3K-AKT and Nrf2-HO-1 pathways in intestinal inflammation is identified.

## Key findings

- Danthron reduces oxidative stress and inflammation in macrophages and intestinal cells.
- Danthron improves colitis in a DSS-induced mouse model by reducing inflammation and enhancing tissue repair.
- Danthron interacts directly with proteins in the EGFR-PI3K-AKT and Nrf2-HO-1 pathways.

## Abstract

Inflammatory bowel disease (IBD) is characterized by excessive oxidative stress, mitochondrial dysfunction, and persistent activation of pro-inflammatory signaling pathways. Danthron, a natural anthraquinone derivative from rhubarb, has been reported to possess anti-inflammatory and antioxidant properties, yet its regulatory mechanisms in intestinal inflammation remain unclear. In this study, we combined network pharmacology, transcriptomic profiling, cell-based assays, intestinal organoids, and a dextran sulfate sodium (DSS)-induced colitis model to determine the protective effects of Danthron against oxidative injury. Integrated target prediction and RNA-seq analysis identified EGFR–PI3K–AKT and Nrf2–HO-1 as key signaling axes modulated by Danthron. In macrophages and intestinal epithelial cells, Danthron markedly suppressed LPS- or H2O2-induced ROS accumulation, lipid peroxidation, and mitochondrial membrane potential collapse, while restoring superoxide dismutase activity and reducing malondialdehyde levels. Danthron also inhibited M1 macrophage polarization, preserved epithelial tight-junction proteins, and maintained transepithelial electrical resistance. CETSA, DARTS, and molecular docking confirmed direct engagement of Danthron with components of both the EGFR–PI3K–AKT and Nrf2–HO-1 pathways. In vivo, Danthron significantly ameliorated DSS-induced colitis, reducing inflammatory cytokines, epithelial apoptosis, oxidative stress, and myeloid cell infiltration while improving mucosal architecture and enhancing organoid regenerative capacity. These findings demonstrate that Danthron exerts potent antioxidant and anti-inflammatory effects through coordinated inhibition of EGFR–PI3K–AKT signaling and activation of the Nrf2–HO-1 axis, suggesting its promise as a multi-target therapeutic candidate for IBD.