It could be a rogue shinobi from Naruto's past who has been biding his time. This shinobi might have developed a new jutsu specifically designed to target Naruto and make him die slowly. He's doing it secretly to cause chaos in the Hidden Leaf when their hero suddenly passes away.
Perhaps an old enemy of the Sannin resurfaces. This antagonist could see Naruto's attempts to follow in the Sannin's footsteps as a threat. They might target Naruto to get revenge on the Sannin or to prevent a new powerful force from emerging in the ninja world. For example, if there were a group that was once defeated by the combined efforts of the Sannin, they could try to stop Naruto before he becomes as strong as the Sannin were together.
It could be someone who wants to expose Naruto's secret. Maybe a rogue ninja who wants to use this information to create chaos in the village by making the villagers doubt Naruto's intentions.
One possibility could be that Naruto has been poisoned by a new and unknown enemy. This poison is slowly eating away at his life force, and he's trying to hide it from his friends and family so as not to worry them. He might be secretly seeking a cure while still fulfilling his duties as Hokage.
Perhaps a jealous rival. This person might be a male who is threatened by Ed's success or popularity. When they discover Ed is a girl, they could use this secret to try and drive her out of the group or community she's in. They might spread rumors or create problems for her.
Maybe there's a dark wizard who has a vendetta against Natsu's family. When he finds out that Natsu is secretly a girl, he sees it as an opportunity to further his evil plans. He could try to kidnap her or use her as a bargaining chip against her family or friends. He might think that because she's a girl, she'll be easier to manipulate or capture compared to if she was thought to be male.
It could be a powerful alien warlord who wants to use the dying reader's unique energy for his own evil purposes. Since the reader is in a vulnerable state, this antagonist sees an opportunity to gain power.
Maybe it's a powerful enemy from outside the village who has infiltrated the bingo book system. They see Naruto as a major threat to their plans and so secretly added him to the book, so they can send their minions to take him out without raising too much suspicion.
Perhaps a rogue Frontier Brain who has his own ideas about how the Frontier should be run. He might see Ash as a threat to his plans, especially if Ash is secretly learning so much about the Frontier Brains. This antagonist could try to sabotage Ash's journey and his secret training.
He could secretly marry Hinata. In the original series, they have a connection, so in fanfiction, it could be a scenario where they elope or have a secret ceremony for some reason, like to avoid political interference in their relationship.
There's no way to tell just from the title. It could be written by any fan who has an interest in Sakura - related stories.