I’d call this one the first major limb it's lost. Deaths like Marcia Wallace were big chunks of skin, but Shearer’s definitely a leg—I’ll say the left one for the hell of it—so Zombie Simpsons can keep on going. To stretch the metaphor out a little further: Azaria’s the right leg, Smith and Kavner are the arms, Cartwright’s the torso, and Castellaneta’s the head.
Losing Azaria would be just as big a hit as losing Shearer, but the show could keep on crawling anyway. Smith and Kavner don't voice nearly as many characters as either Azaria or Shearer, so they’re easily replaceable if the need so arises. Cartwright’s work as Bart and several of his schoolmates is why I put her as the torso(/heart), but even she could be replaced by her non-union Mexican equivalent if Fox really wanted to pinch pennies. Losing anything below the metaphorical neck would be a huge blow to Zombie Simpsons, but it could still keep going regardless.
I feel like Castellaneta is pretty much the only one Fox can’t outright replace. His work as Homer could be duplicated, but it wouldn’t feel the same no matter how good the mimicry is. If he goes, The Simpsons
is likely to go with him.
Looking at the ages of the remaining Simpsons Six, Kavner might be the next to go, given her age (64) and Shearer's age at the time of his firing (71). Castellaneta and Cartwright are both 57, while Azaria and Smith are both in their early 50s. But who knows—given Shearer’s firing and how the show’s run might stretch into an actual third decade, the other main cast members might already be weighing their options.