2. Academic Validation
  3. The transcription factor MEF2C restrains microglial overactivation by inhibiting kinase CDK2

The transcription factor MEF2C restrains microglial overactivation by inhibiting kinase CDK2

  • Immunity. 2025 Apr 8;58(4):946-960.e10. doi: 10.1016/j.immuni.2025.02.026.
Xiaodan Hu 1,  Jianchen Wu 1,  Lu Shi 2,  Folin Wang 1,  Kezhang He 1,  Pengcheng Tan 1,  Yanyan Hu 1,  Yuanyuan Yang 1,  Dan Wang 1,  Tianhua Ma 3,  Sheng Ding 4
Affiliations

Affiliations

  • 1 New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 2 CRE Life Institute, Beijing 100000, China.
  • 3 New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. Electronic address: matianhua@tsinghua.edu.cn.
  • 4 New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: shengding@tsinghua.edu.cn.
PMID: 40139186 DOI: 10.1016/j.immuni.2025.02.026
Abstract

Microglial intrinsic immune checkpoints are essential safeguards to maintain immune homeostasis by preventing microglial overactivation, a process that substantially influences neurological disorders such as autism spectrum disorder (ASD). MEF2C is a crucial immune checkpoint that regulates microglial activation, but the mechanism remains unclear. We found that MEF2C-deficient (MEF2C-/-) induced microglia-like cells (iMGLs) derived from human pluripotent stem cells (hPSCs) exhibited overactivation following lipopolysaccharide stimulation, mimicking patterns observed in various neuroinflammatory disorders. High-throughput screening identified BMS265246, a cyclin-dependent kinase 2 (CDK2) inhibitor, which suppressed overactivation of MEF2C-/- iMGLs and normalized their inflammatory responses. Mechanistically, MEF2C transcriptionally upregulated p21 to inhibit CDK2 activation-mediated retinoblastoma protein (RB) degradation, thereby preventing transcription factor nuclear factor κB (NFκB) nuclear translocation and consequent microglial overactivation. BMS265246 treatment substantially ameliorated microglial overactivation and ASD-like behaviors in Mef2c-deficient mice. Our findings identify the MEF2C-p21-CDK2-RB-NFκB axis as a critical pathway to maintain microglial homeostasis and highlight CDK2 as a potential therapeutic target for neuroinflammation.

Keywords

ASD; CDK2; MEF2C; immune checkpoint; microglia; neuroinflammation; neurological disorders.

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