Perhaps an ancient and malevolent spirit. This spirit might have been awakened by the Winchesters' activities and decides to target Dean. By making him forget his humanity, the spirit hopes to create chaos and destruction. The spirit could be using Dean as a pawn in its grand scheme to cause mayhem in the world of the living.
One possible plot could be that Dean suddenly wakes up one day with no memory of his humanity. He might start exhibiting strange behaviors, like not understanding emotions or basic human needs. For example, he could be confused by the concept of hunger or sleep. His friends would then have to find a way to help him remember who he really is, perhaps by taking him to places that hold significant memories for him.
It could be a rogue ninja who has a vendetta against Sasuke. This ninja knows that Naruto's bond with Sasuke is strong, so he uses a special jutsu to make Naruto forget Sasuke, hoping to break Sasuke's spirit. By removing Naruto from Sasuke's life in this way, the rogue ninja believes he can defeat Sasuke more easily.
It could be a witch who cast the spell that turned Dean into a girl. This witch might have some ulterior motives, like using Dean's new form to disrupt the balance in the hunting world. Maybe she wants to create chaos among hunters by making them question Dean's abilities now that he's a girl.
It could be a dragon hunter who sees Dean as a dangerous abomination. This hunter might have a personal vendetta against dragons and doesn't care that Dean was once human.
It could be a new vampire who is jealous of Bella's relationship with the Cullens. This vampire might have some special power that allows them to manipulate memories, like Alice's memories of Bella. They see Bella as a threat to their own plans in the vampire world, so they try to create chaos by making Alice forget about her.
It could be another ghost who is jealous of Casper's new human form. This ghost might try to sabotage Casper's attempts to fit into the human world, perhaps by causing chaos around him and making humans afraid of him again.
It could be a vampire who resents Damon for becoming human. This vampire might see it as a betrayal of their kind. They could try to either turn Damon back into a vampire against his will or simply make his human life miserable.
The main antagonist could be a dragon hunter. Since Saphira is now in a human form and has lost her dragon defenses, the hunter sees her as an easy target. He might be after her because he believes that she has some connection to the dragons and he wants to use her to find the dragon lair or something valuable related to dragons.
It could be another monster who is jealous of Sans' new form. This monster might feel that Sans is getting special treatment or opportunities because he's now a human. So, this jealous monster tries to find a way to either turn Sans back into a skeleton against his will or make his human life miserable by causing trouble for him in the human world, like spreading false rumors about him.
Dr. Eggman would be an obvious choice. Since Sonic is now in a more vulnerable human form, Eggman could see this as the perfect opportunity to finally defeat Sonic and take over the world. He might come up with new devious plans, like creating robots specifically designed to target a human Sonic.