The Akatsuki could also serve as antagonists. Even if Itachi was once part of them, they might target Sakura to get to Itachi or to use her skills for their own evil purposes. Their goals of collecting tailed beasts and causing chaos in the ninja world would clash with Itachi and Sakura's efforts to protect the village and each other.
Some fanfictions might introduce new original antagonists. These could be powerful rogue ninjas who are after Sakura for her medical skills or some special power she might have in that particular fanfiction. They would then be the main threats that Itachi has to deal with to protect her.
It could be rival assassins. They might see Sakura as a threat to their own business or reputation in the assassin world.
It could be some of her jealous peers. For example, those who are envious of Sakura's skills or her closeness to certain important characters in the Naruto universe. They might spread malicious gossip about her to make her an outcast.
A rogue ninja who wants to steal the power of the contract for his own evil purposes could be the main antagonist. He might be jealous of the connection between Sakura and Itachi and wants to break it to gain the abilities they could potentially unlock together.
One possible antagonist could be a popular girl in school who is jealous of Sakura's popularity and tries to undermine her at every turn. For example, she might spread false rumors about Sakura or try to steal her friends. Another could be a strict teacher who doesn't believe in Sakura's abilities and is always giving her a hard time, like constantly doubting her work in class or not allowing her to participate in certain school activities.
It could be Orochimaru. Even though he was defeated before, he might come back with a new plan. Maybe he wants to use Naruto and Naruko's family for some dark experiment, like trying to extract the unique chakra combination that their family might have.
It could be the Akatsuki. Even though Itachi was once part of them, now that he has the power of a Jinchuriki, they might see him as a threat. They could want to capture him to either extract the tailed beast or to stop him from using its power against them.
The Akatsuki could be antagonists. They might see Sakura being trained by Madara as a threat to their plans. Since Madara has his own motives and is associated with the Akatsuki, they could fear that Sakura will become a powerful force against them if she is fully trained by him.
Another possibility is a rival clan. They might target Sakura specifically because she is seen as a rising star within her clan and they want to undermine her clan's strength. For instance, they could try to kidnap her or spread false rumors about her to create discord within her clan.
One possible main antagonist could be a shinobi from another village who fears Sakura's potential as Hokage. This shinobi might try to undermine her by causing chaos in her village or spreading false rumors about her abilities. Another could be someone within her own village who has a long - standing grudge against her or her family and doesn't want to see her in a position of power.