Here are the super special keywords if you know what you're doing with Wine: Wine 9.0+ (otherwise the newest MO2 doesn't work), winetricks vcrun2022 dotnet48 faudio, install .NET 7.0 SDK manually with the exe. Set up a prefix with those components and you can run all the modding tools. Don't bother with the convoluted MO2 installer script.

Synthesis was having issues compiling patches using the latest Kron4ek wine builds, so I started using the latest Proton-GE and that resolved it. I'm not sure if Wine-GE would have fixed the same problem, but Wine-GE is no longer being updated, and we need at least 9.0+. Install Proton-GE for Steam through e.g. ProtonUp-Qt, and then Lutris can select it as a runner option and will run it through the new UMU project.

I use Lutris to create and run the prefix, and I have an isolated copy of Skyrim that is patched with Goldberg emulator because I find that easier to manage so it's not at risk of being auto-updated by Steam. If you use a Steam copy directly you probably just need Protontricks and do the same thing.

To capture NexusMods links to MO2, I made an application in my start menu and told Firefox to use it to handle nxm links:

Env Variables: WINEESYNC=1 WINEFSYNC=1 'WINEPREFIX=/mnt/Games/The Elder Scrolls V - Skyrim/Prefix/'

Program: /home/user/.steam/steam/compatibilitytools.d/GE-Proton9-7/files/bin/wine

Arguments: '/mnt/Games/The Elder Scrolls V - Skyrim/Prefix/drive_c/Games/ModOrganizer2/nxmhandler.exe' %u

Note that allowing the nxmhandler.exe call to start MO2 is bad because it won't start with the special UMU launcher framework, but if MO2 is already running it's fine.

Performance is great, and everything "just works" with MO2. My only issue is that Pandora and Synthesis (at least) sometimes do not seem to end their process appropriately after running, so I sometimes need to manually stop them via a process manager.