Abstract .Embryonic stem cells (ESCs) can be maintained in the na?ve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the na?ve state. Here, we use mass spectrometry to describe the molecular events (phosphoproteome, proteome, and metabolome) trig...