Chief rail route in Milan running east (8)
I believe the answer is:
mainline
'chief rail route' is the definition.
(mainline can mean an important railway line)
'in milan running east' is the wordplay.
'running' is an anagram indicator (the letters run around to different places).
'east' becomes 'e' (abbreviation).
'in'+'milan'='inmilan'
'inmilan' with letters rearranged gives 'mainlin'.
'mainlin'+'e'='MAINLINE'
(Other definitions for mainline that I've seen before include "use drug" , "Inject drug - principal rail connection" .)