So, as a longtime player, I'm used to using the keyboard commands, but sometimes they require more fingerwork than feels comfortable when doing things repetitively, and it gets tiring.
One example is the Look command, because the situation in which I commonly use that is when I'm wandering around villages looking for something to buy. Its simpler than it used to be, because now you can select a target and then move the target on to the next item, and the next. But, I'm still moving my right hand up from the arrow keys to the L key; so there's still a tendency of me just wanting to move over the items to see what they are instead of using the Look command, because that would require me to lift my fingers up.
It would be a lot simpler, say, if I could press something close to the arrow keys, like the Shift key. On my keyboard, Shift is close to both the arrows and the numpad -- so, using either, I could pivot to Shift without much tedious fingerwork. Another possibility is using the Space key, because even though its not next to either the arrows or the numpad, I can at least use it with my left hand, and don't need to move my right hand. My preference for this kind of quick access is the Shift key.
In any case, this would be "Look mode".
Then, from there, it seems to me you can simplify some other common activities. For example, there are common reasons you would want to look at an NPC or animal: to determine who to talk to, or determine who to attack. It would simplify things greatly if once the Info Box came up with the description of the NPC or animal you're looking at, you could press the commands to chat (C) or attack (1 or 2 or T for throw) immediately, without having to retarget the NPC or animal, by pressing Esc, then pressing Esc again, then C or 1 or 2 or T, and then Enter a second time. Or if not at the Info Box, then at the targeting cursor. This would get rid of one or two keystrokes.
You would of course have to determine for directional attacks whether the target is next to the player. If that's done, though, he same mechanics could also apply to things like picking up or moving things, though. So you could go into Look, and if you find the right pile of things, you can then press the , key to pick something up without exiting Look first.
These are just my suggestions, but I think they would reduce hand fatigue.