Out of left field guess: a reboot to get around the rights issues...
I can't imagine that. They've invested too much and Superman is so much a part of the DCU that it would mess up virtually all of DC's other titles; they might as well close up shop.
Similarly, if they decide to "reimagine" Superman in any permanent way, DC is finished. Superman and Batman are utterly untouchable - expected tweaking notwithstanding. But if they were to, say, turn Superman into a villain or something, they'd be killing themselves. (As it is, if they ever canceled either Action Comics or Detective Comics, I'd be seeing that as the beginning of the end).
I could see something like Superman and Lois divorcing. One subplot that's been going on for years is the attraction between Superman and Wonder Woman. Perhaps some infidelity?
Only thing is that's really too soap-opera. I'm sure they won't make him gay or anything - that would just be stupid after years of him fawning over Lois (not to mention WW).
If I had to make a guess. And I'm not spoiler-coding this because I'm not referencing any storylines currently underway. Ever since Day 1 (as in 1938) a lot has been made about Superman never killing anyone intentionally. It's been a recurring plot point, and in the aftermath of WW killing Maxwell Lord DC - rather admirably, I thought - spent an extensive amount of time discussing Superman's philosophy and how other DCU characters agreed or disagreed with it. The current World Against Superman, which has him leading the Kryptonian military (that's not a spoiler because it's splashed all over the covers) has reignited some of that discussion.
I think Superman is going to pull a Maxwell Lord on somebody. And while to an extent that's a retread of the whole WW-as-killer subplot that dominated Infinite Crisis, it would have a fresh approach because this is Superman we're talking about.