It could be a rogue ninja who has a grudge against Naruto. This ninja might have developed a special jutsu that can manipulate memories. He uses it on Naruto's friends to make them forget Naruto, hoping to isolate and break Naruto's spirit.
Maybe an old enemy of the Hidden Leaf Village. They see Naruto as a symbol of the village's strength. By making his friends forget him, they aim to weaken the village. This enemy could be someone from a long - forgotten clan who has been planning revenge for years and finally found a way to target Naruto through his friends' memories.
It could be a jealous relative who wants Naruto out of the picture so they can have more attention or power within the family.
The plot might involve a curse. Naruto could be cursed by an ancient power. As a result, his friends' memories of him start to fade away. He might notice this when they stop responding to him as they used to. Naruto would be heartbroken but determined. He could search for the origin of the curse, facing many challenges along the way. And in the process, he might discover some long - lost secrets about his own family or the ninja world that are related to this curse.
Maybe it's an evil organization that wants to isolate Naruto. By making his family forget him, they hope to break Naruto's spirit and prevent him from becoming a powerful force in the ninja world. So they target his family's memories as a way to get to him.
Well, there could be characters like Iruka - sensei. Since Naruto has been forgotten by his parents, Iruka might play an even more important role in Naruto's life, becoming like a surrogate father figure. Another character could be Sasuke. Sasuke, who also has his own family issues, might either be a source of understanding for Naruto or a contrast to his situation.
It could be a demigod who was once shunned and now wants revenge. This demigod has turned to the dark side and uses their powers in a twisted way to cause chaos among the other demigods. They might target the forgotten demigod specifically because they see them as a symbol of all that is wrong with how demigods are treated.
It could be Mysterio. He's always been jealous of Peter's connection to Tony. He uses his illusions to mess with Tony's mind and make him forget Peter. Mysterio wants to be the one in the spotlight and sees Peter as an obstacle, so by making Tony forget him, he can get rid of Peter's influence on Iron Man.
It could be Orochimaru. He's always interested in new forms of power and experimentation. He might see Wolverine as an interesting specimen to study and try to extract his healing factor or adamantium for his own purposes. This would put him in direct conflict with both Wolverine and Naruto, who would naturally oppose Orochimaru's evil plans.
Danzo could be a great main villain in a Naruto Frankenstein fanfiction. He's always been power - hungry and secretive. He might use the concept of creating a Frankenstein - like being to gain more power for Konoha in his own twisted way, but really it's all about his own control. He could be using parts of dead ninja's abilities or something like that, and Naruto would have to stop him.
Orochimaru could be a likely main villain. He has always been interested in Naruto's power and body. Maybe he finally devises a plan to kidnap Naruto and use his body for his own reincarnation experiments.
It could be Orochimaru. He might be interested in stealing the exosuit to enhance his own powers and immortality research. He could see the exosuit as a new way to achieve physical enhancements beyond what his current jutsu can do.