The 'massive war, large areas uninhabitable, life twisted into strange and terrifying forms' really reminds me of the setting of "This Immortal" by Zelazny. Basically, on a future earth, every major landmass has been nuked, and humanity is living on the fringes, mainly untouched coastlines and islands (and also as second-class immigrants on other planets). Any place that doesn't consist entirely of radioactive mud is populated by mutants, either animal in origin or not-quite-human. Strangely, some of these mutants resemble mythical creatures, to the extend that mainland Greece is filled with fauns and pegasi and stuff.

Now replace 'nuke' with 'magical obelisk'. The obelisks were designed to protect the empire, but something went wrong and they warped the surrounding lands, or just blew up. Humanity is safe outside of the field of influence of the obelisks, but once they come too close something unpleasant happens, even if it's just being attacked by warped creatures. Maybe one obelisk shifted a city to the elemental plane of fire, while another simply exploded and scattered 'radioactive' chunks of magic crystal/metal/concrete across the countryside, and yet another plunged a large island into the ocean. Maybe there are still 'warp storms' raging around the larger obelisks. Humans affected by the obelisk are not necessarily evil, but most are rather 'off' compared to untouched humans, and are maybe more than a little distrustful towards the people that made them that way. Others are really just out to kill you, and others aren't really human but are just pretending to be, again, to kill you. Then there are the huge amounts of warped animals who are just really, really hungry. Possibly, most magical ability is a direct result of being exposed to the magical obelisks, and 'pure' humans are not natively able to do magic, and, somewhat rightly, fear it. Some newly established (island) nations simply refuse to allow anything magical to cross their borders, while others have little option but to endorse it to defend against magical enemies.

So we have humans living in remote areas, being disliked by the majority of the demihumans, hunted by monsters and fearing magic. Most of the continent is really dangerous, or outright lethal. Adventurers instead seek out these dangers to get their hands on magical items and arcane secrets. It sort of goes along with the 'points of light' shtick of 4E, but it goes a little deeper than 'outside is scary, there's, like, monsters and stuff'.