My first thought on the centering of the wheels is that they were never centered from the factory. So it should not be worrisome from a safety standpoint.
I'd get the bed in the right place, decide if I were going to change fenders or not, and then move the fenders to center over the wheels.
I'm not sure what it would take to move the bed sides down while not moving the floor, but yes that approach should solve that part of the problem. It may be as easy as removing the wood and then moving the angle pieces along the side up whatever the desired amount would be, and then putting it all back together.
But if you do that your tailgate will open below the bed floor and that would bother me.
