The most profitable seems to be the lines which connect 2 cities only. So on a circle track between cities like A-B-C-D-A, add lines for A-B, B-C, C-D and D-A.
I usually run 2 trains on each line first. It will take a while before they get profit, so if you’re low on cash, do not add all trains at once as it will cost you 😉
I still didn’t get to a point where I felt I could add a line from A-C and/or B-D because of the lag in the game (also the reason I build this configuration multiple times as I just needed to start a new game). As this problem has mostly been solved, I’m getting there now. I’ll let you know my experience.
The real cash-cows are tram/bus lines between cities. You can add many, many trams and/or buses and they will make you millions. I use this to make money first for building the tracks and stations. Then I start with the train-lines, replacing the tram/bus connections. I think you eventually need to replace them, as the lines become to crowded and the cities to busy to handle all of this road-traffic. It also seems to make sense, doesn’t it?