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AMPK activation alleviated dextran sulfate sodium-induced colitis by inhibiting ferroptosis
Shao Peng Sun1, Yi Fan Lu1, Heng Li1
1The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.
Objectives:
Ferroptosis is a newly discovered cell death mode that has been confirmed to occur in the intestinal epithelial cells in ulcerative colitis (UC). In this study we aimed to elucidate the mechanism of ferroptosis and its association with adenosine monophosphate-activated protein kinase (AMPK) in UC.
Methods:
Gene expression profiles of colonic mucosa (GSE87473) were downloaded. Both human colonic samples and dextran sodium sulfate (DSS)-induced colitis murine model were used. The molecular markers of ferroptosis were detected using western blot and immunohistochemistry. Symptoms, iron abundance, and lipid peroxidation level of the mouse model were measured to evaluate the role of AMPK activation in ferroptosis.
Results:
Both gene and protein expressions of GPX4 and FTH1 were decreased in UC patients compared with the healthy controls. An increased iron abundance and lipid peroxidation level in colon tissues and damaged mitochondria were found in DSS-induced colitis. AMPK expression was decreased in UC patients and correlated with FTH1 and GPX4. Activation of AMPK with metformin inhibited ferroptosis in the colon, improved symptoms, and prolonged the lifespan in DSS-induced colitis mice.
Conclusions:
Ferroptosis can be observed in colonic tissues in UC. AMPK activation inhibits ferroptosis in murine colitis model, which may act as a potential target for the treatment of colitis.
Insights
Ferroptosis, a cell death pathway, occurs in ulcerative colitis (UC). Activating adenosine monophosphate-activated protein kinase (AMPK) inhibits ferroptosis in colitis, suggesting it as a potential therapeutic target.
Area of Science:
- Cell biology
- Gastroenterology
- Biochemistry
Background:
- Ferroptosis, a regulated cell death, is implicated in intestinal epithelial cells of ulcerative colitis (UC).
- Understanding the mechanisms of ferroptosis and its regulators in UC is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of ferroptosis and its association with adenosine monophosphate-activated protein kinase (AMPK) in ulcerative colitis (UC).
- To explore the therapeutic potential of targeting AMPK in UC-related ferroptosis.
Main Methods:
- Analysis of colonic gene expression profiles (GSE87473) from UC patients and healthy controls.
- Utilized human colonic samples and a dextran sodium sulfate (DSS)-induced colitis murine model.
- Assessed ferroptosis markers (GPX4, FTH1), iron levels, lipid peroxidation, and mitochondrial integrity; evaluated AMPK activation effects using metformin.
Main Results:
- UC patients and DSS-induced colitis mice exhibited decreased GPX4 and FTH1 expression, increased iron, and lipid peroxidation.
- Reduced AMPK expression was observed in UC patients, correlating with FTH1 and GPX4 levels.
- Metformin-induced AMPK activation suppressed ferroptosis, alleviated colitis symptoms, and improved survival in mice.
Conclusions:
- Ferroptosis is a significant feature in the colonic tissues of UC patients.
- AMPK activation demonstrates a protective effect against ferroptosis in a murine colitis model.
- AMPK represents a promising therapeutic target for managing ulcerative colitis.
