Fibroblast-specific Gpx4 deletion exacerbates IBD via lipid peroxidation

Area of Science:

• Gastroenterology
• Cell Biology
• Immunology

Background:

• Antioxidant therapies for inflammatory bowel disease (IBD) show limited efficacy due to indiscriminate reactive oxygen species (ROS) quenching.
• Fibroblast-specific acyl-CoA synthetase long-chain family member 4 (ACSL4) overexpression sensitizes epithelial cells to ferroptosis in IBD models, highlighting lipid crosstalk in epithelial injury.

Purpose of the Study:

• To investigate the role of fibroblast glutathione peroxidase 4 (GPX4) in limiting lipid peroxidation and epithelial ferroptosis during colitis.
• To determine if targeting fibroblast GPX4 or lipid peroxidation can ameliorate colitis-associated injury.

Main Methods:

• Generated tamoxifen-inducible fibroblast-specific GPX4 knockout mice.
• Induced acute dextran sulfate sodium (DSS) colitis in knockout and control mice.
• Assessed colitis severity via histological scores, weight loss, and colon length.
• Utilized in vitro ferroptosis assays with GPX4-deficient fibroblasts and liproxstatin-1 treatment.

Main Results:

• Fibroblast-specific GPX4 deletion aggravated DSS-induced colitis, increasing injury severity, weight loss, and colon shortening.
• GPX4-deficient fibroblasts showed increased lipid peroxidation, which was reversed by liproxstatin-1.
• Liproxstatin-1 treatment rescued colitis severity in fibroblast-GPX4-deficient mice.

Conclusions:

• Fibroblast GPX4 acts as a critical gatekeeper, suppressing stromal lipid peroxidation and epithelial ferroptosis under inflammatory stress.
• Targeting fibroblast-mediated lipid peroxidation presents a potential refined therapeutic strategy for IBD.