MEF2C Alleviates Postoperative Cognitive Dysfunction by Repressing Ferroptosis

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Postoperative cognitive dysfunction (POCD) is linked to ferroptosis, a cell death pathway involving lipid peroxidation.
• Myocyte-specific enhancer factor 2C (MEF2C), a transcription factor, is involved in cognitive processes and brain function.
• The role of MEF2C in POCD and its connection to ferroptosis remain unclear.

Purpose of the Study:

• To investigate whether MEF2C influences cognitive function after surgery by modulating ferroptosis.
• To explore the therapeutic potential of targeting MEF2C for preventing POCD.

Main Methods:

• Transcriptomic analysis identified MEF2C as differentially expressed in POCD mouse hippocampus.
• A POCD mouse model was created using anesthesia and surgery, with manipulated MEF2C and GPX4 inhibitor (RSL3) levels.
• Cognitive function, cell damage markers, ferroptosis indicators, and MEF2C's transcriptional regulation of GPX4 were assessed.

Main Results:

• MEF2C levels decreased in the hippocampus post-surgery and anesthesia.
• Overexpressing MEF2C improved memory, reduced lipid peroxidation and iron accumulation, and boosted antioxidant capacity.
• MEF2C directly activated GPX4 transcription by binding to its promoter, an effect reversed by RSL3.

Conclusions:

• MEF2C plays a protective role against POCD by suppressing ferroptosis.
• MEF2C's ability to transcriptionally activate GPX4 is key to its neuroprotective effects.
• MEF2C represents a potential therapeutic target for mitigating POCD.