Elissa's father's death. For a child to have to watch her father suddenly drop dead in front of her from an aneurysm is really heart-breaking.
Thugboy losing all his friends twice: first when his cell of the capeless uprising in San Antonio got wiped out, and then again when his gang of Witless Minions was raped to death by Willy Pete. Add to that the fact that his mother and sister apparently both died under still unknown circumstances, and this guy has had a truly heartbreaking life up until he met Elissa.
Ninjette's whole childhood, really. Her mother apparently died when she was very young, for which her father blamed her. More generally, her father was an abusive drunk ninja who just made her life absolutely miserable. Furthermore, she was never allowed to have any friends, even within her own ninja clan. When you realize that Elissa is the first friend she ever had in her life, it's hardly any wonder that she is an alcoholic—a high-functioning alcoholic, but still, an alcoholic, as she admits to herself at the end of Nine Beers with Ninjette.
The scene when Anglerfish tells Emp about the murder of his son by Willy Pete. Anglerfish and his son may have both been supervillains, but you cannot help but feel for a man who has lost his son to such a horrible crime.
Not that he didn't kind of deserve the beatdown he got from Emp, having put the poor girl through her deepest desires to be appreciated and see her father again only to have them ripped away harshly. Her reaction to being bound by who she thinks is her own father (after hoping she wasn't a disappointment to him no less) is absolutely heartrending.
Mindf**k's death. One of the nicest superheroes by far, and one of the few to make any real effort to befriend Emp, and she dies even after Emp manages to get her safely to the evacuation portal, and Sistah Spooky flies up to save her. And if that were not enough, she's not even all that sorry to die, because of how unhappy her life had been. To top that off, for all she tries to tell Spooky that she should believe that she deserves to be loved, she can't really bring herself to believe that she really is a good person.
The final chapter of Empowered 5. Mindf**k's Heroic Sacrifice is bad enough, but the following scene with Emp and Sistah Spooky is just heartbreaking.
Volume 6, oh gods. "What does "three seconds too late" mean, Spookums?"
Volume 8, Mindf**k's in Hell. Spooky and Emp didn't save her. That's where she will almost certainly stay. Nothing more needs to be said about it.
Also the revelation that a lot of Emp's reputation and her tendency to get tied up are Spooky's fault due to spells cast in fits of jealousy. And Spooky tried to undo it a long time ago and can't because of how strongly the urge to subject Emp to bondage has become ingrained for villains.Cosmic Plaything much?