Title updates (and sometimes small content updates) cause all sorts of panic, so the goal of this guide tell you how these updates affect modded files and how to get things working again.
To do this, I have to tell you how modded files are loaded in the first place because how/why they work is the crux of the issue.

If you just want general reset instructions to get things working, skip to the end.

MHR looks for files/content in two places:

• The game paks.
  • In numerical order, incl. patches.
• The natives folder.

MHR will always check the pak first, and only check in natives if it can't find the file in the pak.

The pak is essentially an archive in a proprietary format.

There are two primary ways of loading files:

• Fluffy Manager
• First Natives

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Fluffy Manager copes the files to natives, then invalidates the paths of the copied files in the pak.
This means Fluffy is directly altering the pak so as to mark the copied files as "not being in the pak". As we said above, MHR will only check natives if it can't find it in the pak. If we alter the pak so the file appears missing, the game will happily move onto the next pak in sequence and eventually natives.

So when Fluffy is working properly, it's altering every game pak to mark the installed files as "not here".

Every time the game updates the paks (adding new content and such) the paks are reset to their initial unaltered state.
This means the modded files are left in the game dir, but the game won't load them because nothing told it to.

You have to uninstall all modded files, re-read game archives, then install them again to get things working again.

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This one doesn't use paks. First Natives (FN) is a REFramework plugin (dll) that forces MHR to check the natives folder before the paks.

This means game updates will NOT reset their installed state because the paks were never altered.
This is why FN is considered 'cleaner' than pak methods.

This also gives you the ability to rename/move files directly in natives without having to close the game first or reinstall anything.
With Fluffy, you can only alter paks when the game is closed, you also have to uninstall then rename/change mod files then reinstall. This becomes a PITA to deal with esp. when developing mods due to the extra steps.

But FN isn't bulletproof in updates and sometimes breaks like it did in TU4.

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Fluffy:

• Is a mod manager.
• Can alter paks so mods load.
• Things get reset when the game releases.
• Needs to close game & uninstall/reinstall mods if any part of the mod path needs to be altered.

First Natives:

• Is not a manager.
• Is just a file loader.
• Things still work after content updates (usually).
• Can just directly rename/move things in natives without restart. (Some files don't take affect till the game is restarted, but most visual mods can work without restarting.)

But you can use both and get the best of both worlds!
It is possible to use Fluffy without altering paks, which gives you a great manager combined with a great loader. This is due to the "skip pak modding" option in advanced settings.
(If you're just turning this option on though, it's better to uninstall all mods first so the paks are reset/pristine first.)

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The easiest way to clean do a clean install is:

• "Uninstall all" in Fluffy. This should remove all files in the natives folder in the game dir. If it didn't, you have something leftover from some other install or maybe even Vortex. I would remove it to start fresh.
• Validate files in Steam.
• Re-read game archives in Fluffy.

If you want to use FN to load files:

• Turn on the "Skip pak Modification" (Advanced Option) in Fluffy.
• Install FirstNatives.
• Re-install mods. Activate one by one if you need to to find which is causing your issue.

If you want Fluffy to alter paks to load files:

• Turn off the "Skip pak Modification" (Advanced Option) in Fluffy.
• Re-install mods. Activate one by one if you need to to find which is causing your issue.

TU4 broke FN, so unless it's been updated since, follow the latter Fluffy instructions.

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These tend to not get broken by game updates, but themselves are loaded by REF. So as long as REF is working, these will load, even if they aren't compatable with the new update.

The easiest way to clean these is either:

• Rename/remove dinput8.dll (the REFramework dll). This disables REF completely.
• Remove the LUA mods from reframework/autoruns/.