public string Expression {get; set;}

var lyr = MapView.Active.Map.GetLayersAsFlattenedList().OfType<FeatureLayer>().FirstOrDefault(f => f.ShapeType == esriGeometryType.esriGeometryPolygon);
if (lyr == null) return;
QueuedTask.Run(() =>
{
  //Get the layer's definition
  //community sample Data\Admin\AdminSample.aprx
  var lyrDefn = lyr.GetDefinition() as CIMFeatureLayer;
  if (lyrDefn == null) return;
  //Get the label classes - we need the first one
  var listLabelClasses = lyrDefn.LabelClasses.ToList();
  var theLabelClass = listLabelClasses.FirstOrDefault();
  //set the label class Expression to use the Arcade expression
  theLabelClass.Expression = "return $feature.STATE_NAME + TextFormatting.NewLine + $feature.POP2000;";
  //Set the label definition back to the layer.
  lyr.SetDefinition(lyrDefn);
});