Maybe this has been done before, but anybody else dream of haven and hearth variants? Where the basic mechanics are very similar, but the theme is different?
Top of my list would be an East Asian theme. Maybe warring states period Japan. Ancestor worship could be integrated much better with perma death, and politics/warfare and crafting could be quite interesting. Also lots of cool monsters to choose from if you wanted to have a few.
Next would probably be cusp-of-industrialization U.S. (not necessarily historically accurate) Let people enjoy the nitty gritty crafting of basic items for when they are out on the fronteer, only except that it is also possible to build factories, warehouses, railroads etc. Hard to get away from some kind of NPC aspect there to support production/consumption of goods at a scale where you are talking about hundreds of thousands of people though.