Perhaps an old enemy of Tsunade resurfaces and targets Shizune as a way to get to Tsunade. Since Shizune is Tsunade's closest aide, they see her as an easy target to manipulate or harm. This antagonist could use some long - forgotten vendetta against Tsunade as a motivation to create problems for Shizune, which would be a big surprise as no one expected this old grudge to resurface.
There could be a new, mysterious group of ninjas from a far - off land. They view Konoha as a threat and decide to target Shizune as she is an important figure in the medical and ninja community of Konoha. Their motives could be shrouded in mystery at first, and they surprise everyone with their unique and powerful jutsus as they try to take Shizune out of the picture.
It could be a rogue medical ninja who was once a colleague of Shizune but turned to the dark side. This antagonist might be jealous of Shizune's position in the village and her relationship with Tsunade. He or she could try to undermine Shizune's new discovery or training program in the fanfic by causing chaos in the village and framing her for it.
One possible plot could be that Shizune discovers a hidden jutsu in the village archives that has the power to bring back a beloved but lost character. She decides to secretly practice this jutsu and surprises everyone when she successfully brings back the character. This would cause a stir in the village and lead to a series of adventures as they figure out how this new addition will change the dynamics of the village.
There could be a group of villagers who are superstitious. They believe that Shizune's presence in the hospital during a recent epidemic is what made it worse (even though it's completely untrue). Naruto has to comfort Shizune and then he tries to educate the villagers about the real causes of the epidemic and how Shizune was actually helping.
It could be a rogue ninja who has a vendetta against Shizune's family. This ninja might see Naruto as an obstacle in his path to revenge. He could target Naruto to get to Shizune and try to break their family - like bond.
The Organization in the Claymore world could be the main antagonist. They already have a lot of secrets and do some morally ambiguous things. If Naruto shows up and starts changing the status quo, like teaching Claymore warriors to be more independent, the Organization might see him as a threat and try to eliminate him.
It could be a rogue ninja who was once a student of Orochimaru and has now developed his own dangerous jutsu. He wants to take over the ninja world and believes the old ways are holding everyone back.
Orochimaru could be a great antagonist. He might want to use Shenron's power for his own dark experiments. He could try to steal the dragon balls and manipulate the wishes to gain immortality or create an army of powerful, immortal ninja.
It could be someone who opposes Naruto's newfound admiration for Ganondorf. Maybe a traditionalist ninja who thinks Naruto is straying from the true ninja path by getting influenced by Ganondorf.
Lex Luthor could be a great antagonist. He's always looking for power and knowledge. If he discovers Naruto's abilities, he might try to use them for his own gain or see Naruto as a threat to his plans in Smallville.
It could be Orochimaru. He's always been interested in unique powers and abilities. The idea of X - 23's mutant abilities and Naruto's jinchuriki powers would be very appealing to him. He might try to capture them both to use in his experiments to gain ultimate power.
A new character could be created as the antagonist. For example, an Uchiha who has been corrupted by the power of the Sharingan and wants to use Naruto's special Uchiha - related abilities for his own evil purposes. This character could be jealous of Naruto's unique position within the Uchiha - related story and try to take it from him.