Ferroptosis Mechanisms in Inflammatory Bowel Disease

Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation that emerges as a crucial contributor to the pathology of inflammatory bowel disease (IBD). In the healthy gut, a balance between cellular iron handling, antioxidant defences and membrane lipid composition preserves intestinal epithelial cell (IEC) integrity. In IBD, dysregulation of iron uptake and storage leads to iron overload, while depletion of glutathione and inactivation of glutathione peroxidase 4 (GPX4) undermine the cellular capacity to detoxify lipid hydroperoxides. The resulting accumulation of reactive oxygen species (ROS) and lipid peroxides damages cell membranes, disrupts epithelial barrier function and exacerbates mucosal inflammation. Key ferroptotic regulators—such as the cystine/glutamate antiporter system Xc−, ferroptosis‐promoting enzymes (for example ACSL4) and endoplasmic reticulum stress pathways—intersect with inflammatory signalling networks including NF-κB, amplifying tissue injury. Understanding these interconnections highlights ferroptosis not only as a pathogenic mechanism in ulcerative colitis and Crohn’s disease but also as a target for novel therapeutic strategies aimed at restoring redox balance and mucosal integrity.

Research from Nature Portfolio

A foundational investigation revealed that dietary enrichment with ω-6 polyunsaturated fatty acids triggers lipid peroxidation in small intestinal epithelial cells exhibiting diminished GPX4 activity. In a mouse model lacking one allele of Gpx4 in IECs, a Western-style, PUFA-rich diet induced focal neutrophilic enteritis mirroring aspects of human Crohn’s disease. This work identifies dietary PUFAs as modulators of GPX4‐restricted ferroptosis and underscores the enzyme’s central role in safeguarding mucosal health under inflammatory conditions.

Ferroptosis Mechanisms in Inflammatory Bowel Disease publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in inflammatory bowel disease across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A form of regulated cell death characterised by iron-dependent accumulation of lipid peroxides leading to membrane damage.

Lipid peroxidation: Oxidative degradation of polyunsaturated lipids resulting in reactive hydroperoxides that drive ferroptosis.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that reduces lipid hydroperoxides to non-toxic alcohols, thereby inhibiting ferroptotic cell death.

System Xc−: A membrane antiporter that imports cystine in exchange for glutamate, supplying cysteine for glutathione synthesis and antioxidant defence.

Reactive oxygen species (ROS): Chemically reactive oxygen-derived molecules that promote oxidative stress and lipid peroxidation.

Intestinal epithelial cells (IECs): Barrier-forming cells lining the gut mucosa whose ferroptotic death compromises intestinal integrity in IBD.

References

1. Human umbilical cord mesenchymal stem cells derived exosome shuttling mir-129-5p attenuates inflammatory bowel disease by inhibiting ferroptosis. Journal of Nanobiotechnology (2023).
2. Unveiling ferroptosis as a promising therapeutic avenue for colorectal cancer and colitis treatment. Acta Pharmaceutica Sinica B (2024).
3. Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease. Nature Communications (2020).
4. Inhibiting Ferroptosis: A Novel Approach for Ulcerative Colitis Therapeutics. Oxidative Medicine and Cellular Longevity (2022).