# Nrf2/HO-1–dependent inhibition of ferroptosis underlies the antioxidant effects of 5-O-methylvisammioside in colitis

## TL;DR

A natural compound called MeV may help treat colitis by preventing a type of cell death called ferroptosis through a specific antioxidant pathway.

## Contribution

The study identifies a novel mechanism by which MeV protects against colitis via the Nrf2/HO-1 pathway and ferroptosis inhibition.

## Key findings

- MeV reduced colitis symptoms and preserved colon structure in rats.
- MeV inhibited ferroptosis markers like lipid ROS and iron overload.
- MeV's protective effects were reduced when the Nrf2 pathway was silenced.

## Abstract

Ferroptosis contributes to epithelial injury and chronic inflammation in ulcerative colitis, yet pharmacologic strategies that durably attenuate ferroptosis and restore barrier function remain limited. 5-O-Methylvisammioside (MeV) is a natural compound with putative antioxidant properties, but its anti-colitic mechanisms are unclear.

To determine whether MeV alleviates colitis by activating the Nrf2/HO-1 axis and constraining ferroptosis.

Acute colitis was induced in male Sprague–Dawley rats using dextran sulfate sodium and animals were randomized to vehicle, DSS alone, two MeV doses, or mesalazine as a benchmark control. Clinical activity, colon length, and histopathology were quantified alongside epithelial barrier readouts (ZO-1, occludin), oxidative stress and ferroptosis markers (lipid reactive oxygen species, malondialdehyde/4-hydroxynonenal, iron accumulation, GPX4, ACSL4), and Nrf2/HO-1 activation, including nuclear translocation of Nrf2. In parallel, erastin-challenged Caco-2 cells were used to test whether MeV directly restrains ferroptosis; Nrf2 knockdown probed pathway dependency.

MeV dose-dependently reduced disease activity and histological damage and partially normalized colon length. Barrier proteins were preserved, and lipid peroxidation and iron overload were diminished. MeV increased Nrf2 nuclear translocation and upregulated HO-1, restored GPX4, and lowered ACSL4, consistent with ferroptosis restraint. In vitro, MeV limited erastin-induced lipid ROS and cell injury; Nrf2 silencing blunted these protective effects, supporting pathway involvement. Mesalazine produced improvements of similar magnitude on selected endpoints.

MeV alleviates experimental colitis, at least in part by activating Nrf2/HO-1 to restrain ferroptosis and preserve epithelial barrier integrity. These findings nominate MeV as a ferroptosis-targeting candidate for colitis.