i run MO2 through Proton (also you should install protontricks if you don't have it. it helps with additional wine dependencies that may be needed)

then I use MO2 to launch SKSE modded version of the skyrim SE launcher.

Vanilla skyrim runs perfectly with proton kinda on its own, so MO2 doesn't really have to do anything except make sure all the plugins get loaded in the proper order.

MO2 is quite nice, actually. i use it to run the normal Bethesda skyrim.exe if I want to configure my base game settings (graphics etc) but then just exit and swap back to the SKSE launcher from MO2 and we're golden.

I also find that CreationKit seems to play a lot more nicely when launched through MO2 than if I add it to steam and try to manually run it myself with Proton (CreationKit sucks to run, however and you'll have to get used to crashes and losing all progress so I would only recommend using it for very small tweaks.)

but yeah! runs just fine in proton. you really only need MO2 to initially launch skse for you. then it just kinda chills while you're playing. but the software is good (though I will say there was a bit of a learning curve in my case as I am a Vortex refugee 😅)