You can inflict all sorts of terrible stuff on NPCs that it's not cool to do to PCs. E.g., the PCs in one game I'm currently running are students at a school, so inflicting annoying bullying on them is cruel and unusual and potentially triggering of real-life trauma, but inflicting bullying on their NPC girlfriends was perfectly kosher (and then the PCs get to be Big Damn Heroes about it and rescue their girlfriends from the bullying).
Killing beloved NPCs is, of course, a drastic, uncreative, and cliche step. This is most notorious as a phenomenon where every PC begins as an orphan, so the DM can't mess with their family, because some DMs absolutely will have the Big Bad murder every PC family at the earliest opportunity.
But imagine your PC gets word from home that your parents are being extorted, threatened, or have been kidnapped -- at least as effective a motivator of PC action and investment as having the family killed, plus they get the satisfaction of saving their family at the end of the adventure.
It all boils down to a principle I've come to call "Every NPC Is Miles O'Brien", where any time engagement is flagging you throw an "O'Brien Must Suffer" session at the party. (Named after the writers' habit from Star Trek: Deep Space Nine of writing an "O'Brien Must Suffer" episode at least once a season, because Miles O'Brien was the most likeable everyman in a cast full of alien lizard spies and cops made of goo and goofy capitalist aliens and whatnot.)
