I think if you look through the imaginary stories and Elseworlds, you'll probably find a story or two where Lois was a villain. And there were plenty of classic stories where, for reasons, she would turn evil (or pretend to be) as would every single character (Supes, Clark, Supergirl, Linda, Krypto, Comet, Lana, Jimmy, Perry, Ma and Pa Kent).

I also wanted to see the Earth-Three/Anti-Matter Superwoman trade places with Lois. This could have been used as a way to undo the marriage in the Jurgens era. I guess that ship has long sailed.

From the very beginning, Siegel and Shuster could have had Lois as the main villain. She's almost a de facto villain in the way she often treats Clark and/or Superman. It would be interesting to have someone in the main cast who is always plotting against the hero--and someone with whom he's romantically involved.

Or if the Ultra-Humanite's brain had been transplanted to Lois instead of Delores Winters, that would have been a great development.