I've ran a campaign set in the Principalities, where the PCs were all pirates. Well, actually, I ran half of it twice, with one player the same between the groups, since it fell apart halfway through the first time due to group stuff.
Essentially, the idea for the campaign was that the PCs were part of some faction wars going on among the princes. I tweaked the setting a bit, making it not quite as clear that ir'Wynarn is going to rule the Principalities, and organizing different factions so that the PCs could interact with them, and help influence who was going to end up on top. They ended up working for the faction out of Cliffscrape, a combination of dwarven interests from the Mror Holds and a contingent of warforged that ended up there after deserting from the Last War. They were a ship of troubleshooters and pirates for that faction, either making their own decisions or doing stuff based on their patrons.
They ended up dealing with the Inspired quite a bit - the BBEG of the campaign was an Inspiresd psion looking for some artifacts from the original Lhazaar, who the group found in a quasi-King Arthur state, waiting for when the time was right to unite the Principalities under her banner again. They managed to avoid waking her up, and instead got chased around the islands when the Inspired came for 'em. Dealt with an aboleth, several marauding hobgoblin ships, a tribe of lizardfolk in Q'bara, and pushy Deneith admirals. It ended up working out pretty well for what I wanted - a fun, pirate-y game.