Here we found that hyperlipidemia induced by high‐fat diet (HFD) increases the expression of myocyte enhancer factor 2c (Mef2c), a transcription factor regulating cell fate and inflammatory response in ischemic neurons, and found that Mef2c promotes the alternative splicing of Cflar toward CflarR, which consequently aggravated neuronal necroptosis. Here, CFLAR is linked to hyperlipidemia.