Howabout :
Mark Hazzard MERC from the 1986 new Universe line is incorporated into the MU and goes up against Frank. He had a wife and Kid if I remember correctly. Circumstances pit them against each other and Mark ends up being a guy you DONT want Frank to kill, but does, not without a helluva fight though...
On a similar note, Frank is dogged by a man who lost his wife and kids to gun violence. He is a veteran/cop who hates what Frank stands for (and makes excuses for) and is determined to bring him down. He captures Frank and grills him, laying out his flaws..
Return to Baltimore; Frank takes out drug dealers there and comes across the one villain he unknowingly helped get away. A big momma crime boss from a 90's storyline who pinned the blame on her husband whom Frank shot, leaving her to continue her crimes...
ISIS, backpacker bombers, vehicle attack homocides, underage offenders who record their crimes, white supremacists.
Who else?/What else?