Route zero comes up through American state
I believe the answer is:
main line
'route' is the definition.
(main line is a kind of route)
'zero comes up through american state' is the wordplay.
'zero' becomes 'nil' ('nil' can be a synonym of 'zero').
'comes up' is a reversal indicator.
'through' indicates putting letters inside (I've seen this in other clues).
'american state' becomes 'maine' (Maine is an example).
'nil' back-to-front is 'lin'.
'lin' inserted inside 'maine' is 'MAIN LINE'.
(Other definitions for main line that I've seen before include "Way to travel" , "Take 9 intravenously" , "track on which many train" , "Principal rouote of a transportation system" , "Situated on a major route" .)