Mostly, I only have small things I would change from 3E (at least that I can think of this moment), and few of them have much to do with the actual system itself and are easily just house-ruled.
I've always felt that either there should be a Magic Pool that affects all magical skills, or if there's a Spell Pool there should also be a Conjuring Pool. I just think it's fair. I wouldn't mind having something to assist in Enchanting, either, though I don't feel it's necessary.
While on the subject of magicians, I think Astral Projection should be a metamagic option for aspected mages and adepts with astral perception. There's never been a fluff explanation I'm aware of that explains why someone who can partially open themselves to the astral couldn't learn to do so all the way. I also think that being able to use all the magical skills is enough to justify the cost difference between the options.
No Smartgun II. At all. That was such a game breaker.
I would also retcon a lot of stuff from...SOTA 2064 (I think?). Some of the stuff in there just didn't fit, like adepts healing other people.
Also, just say no to things like PANs and tags.
I did really like the skill family thing 4E did. On the one hand, I liked how 3E split up Firearms and Armed Combat into a bunch of skills, but I didn't think the defaulting system worked well for those (but I liked it for anything else). On the other, someone who should be very proficient in, say, all normal firearms (like a merc) has to spend A LOT of skill points in 3E, which I also think is a stretch. So being able to purchase all the skills for some kind of a discount is something I would like to see.
I like there to be an enhanced cost for playing a metahuman. I also liked the flat bonus/penalties to attributes depending on your race, because each race is unique.
Also on the topic of race, I would like reasonable rules for playing a vampire (not in the CRB). I have no clue why 3E introduced a Ghoul option instead, with extensive rules on how you're likely to lose your fraggin' mind. In all honesty, if you were to take away Mist Form, and maaaaaybe limit Essence to 6 instead of 12, a vampire should be no more expensive to play than a shapeshifter. Meanwhile, get pixies, nagas, centaurs, and all that stuff the hell out of here. Have they been around? Yeah. Way, way in the background. They have absolutely nothing to do with the city life of the shadowrun setting, and are very far removed from metahumanity.
Assuming this would be the "new" 4th Edition, it would be the third edition to have a point creation system. Just put it in the CRB. You're not reinventing the wheel, and so many people use it because it's way more flexible than the priority system.
Better Matrix rules, obviously. How? Frag if I know, chummer. I firmly do not believe in wireless decking, though, and I think it's easy to explain away that the matrix is too vast and your brain too complicated to connect the two without a hard connection.
As far as fluff, I want them to STOP sympathizing with what should be black-and-white bad guys for the players. The media shouldn't be trying to gain sympathy for insect spirits. Insect spirits=bad. This should remain clear to everyone, everywhere. Ghouls are largely mindless monsters. You shouldn't have to stop and question "well, how intelligent are they really? Am I being humane?" There are ghouls that retain their humanity, but they're really rare. FAR from being the rule. When I'm reading fluff from people on Shadowland (I want Shadowland back), the majority viewpoint should be hose those suckers down with lead and beat feet before they chow down. Ghouls=don't eat me, bro.
More importantly, as far as fluff, they need to absolutely stop using real world swear words. I'm not interested in picking up a book and seeing casual f-bombs floating around. 1) It takes me out of the setting. 2) If it doesn't serve a reasonable purpose, I'm minorly offended. 3) It limits my ability to share Shadowrun with others, especially the next generation of my family.