It could be a new character entirely. Maybe a rogue ninja from a long - forgotten clan who holds a grudge against Naruto for some past event. This villain could be extremely powerful in dark jutsu and sees Naruto's death as the first step in his plan to take over the ninja world.
Perhaps an old enemy from Naruto's past that was thought to be defeated but actually managed to survive and regain strength. This villain might have a vendetta against Naruto for imprisoning him or causing the downfall of his organization. After Naruto's death, this villain could target Boruto, seeing him as a symbol of Naruto's legacy and wanting to break the will of the Hidden Leaf Village.
There is also a possibility that the main villain is a corrupted version of one of Naruto's friends or allies. This could be due to some dark influence or a tragic event that twists their mind. They could be the one responsible for Naruto's death, either directly or indirectly, and then become the main threat that Boruto has to face in the fanfiction.
One possible plot could be that Naruto sacrifices himself to save Boruto from a powerful new enemy. Maybe an ancient evil resurfaces that is too strong for Boruto to handle alone, and Naruto steps in, using up all his chakra and ultimately dying in the process.
It could be a resurrected Orochimaru. He has always had an interest in power and the Akatsuki. He might return, more powerful than ever, and take control of the Akatsuki in the Boruto era, using them to carry out his evil plans, like creating an army of super - ninjas using some dark jutsu.
It could be Doctor Doom. He might be seeking to take over multiple universes in a crossover. Spider Man stands in his way, and Doom, with his superior intellect and powerful magic, manages to defeat Spider Man. His death would then be a huge shock to other heroes in the crossover, like the Avengers or the Fantastic Four who then have to avenge him.
It could be a new dark wizard who has infiltrated Hogwarts under the guise of a new teacher. This wizard might have a vendetta against Harry specifically and sets up elaborate traps to kill him.
One possible plot could be that Naruto sacrifices himself to protect Boruto from a powerful new enemy. Maybe an ancient evil has been awakened and Boruto is in its direct path. Naruto, being the hero he is, steps in and uses all his power to stop it. His death then becomes a catalyst for Boruto's growth, driving him to become stronger and more determined to protect the village in Naruto's memory.
Most likely, Voldemort would remain the main villain. Without Harry to stop him, he would be free to carry out his evil plans unopposed.
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.