Maybe a new powerful alien race that wants to take over the universe. They might target Goku's sister because they sense her strong power and think that by getting rid of her, they can weaken Goku and his allies. The alien race could have some unique abilities that make them difficult to defeat.
It could be Frieza. Since Frieza has a history of hating the Saiyans, he might see Goku's sister as a new threat and try to eliminate her.
Another possibility is an evil Saiyan who has turned against his own kind. This Saiyan could be jealous of Goku's sister's power or have some grudge against Goku's family. He could try to manipulate Goku's sister or turn her against Goku in order to achieve his own evil goals.
There could be a power - hungry being who wants to use Goku's mother for their own gain. When Goku tries to meet her, this being tries to stop him because they know that if Goku and his mother reunite, they will be able to oppose their evil plans together.
It could be someone who is jealous of their new - found bond. Maybe a rival of Uzumaki who doesn't want him to have such a powerful ally in his sister.
It could be someone who doesn't want Naruto and his sister to unite. Maybe a rogue ninja who fears their combined power. He might try to drive a wedge between them by spreading false rumors or causing misunderstandings.
Maybe an old enemy of Goku's who has somehow managed to return. This enemy has heard about Goku Jr and figures that by attacking him, he can get revenge on Goku. This could be someone like Frieza who has found a new way to be resurrected and is more powerful than ever.
In the fanfiction, Goku might be initially shocked to meet his sister. He could then start to feel a strong sense of protectiveness towards her. Maybe they would train together to become stronger.
It could be an evil ninja who wants to stop Kakashi from meeting his mother. This ninja might be from a rival village and fears that Kakashi will gain some powerful knowledge or ability from his mother that could be a threat to their plans.
The main antagonist might be a dark sorcerer. This sorcerer has put a spell on Spyro's mother long ago, trapping her. He doesn't want Spyro to find her because he fears that together they will be strong enough to break his power. He uses his minions to try and stop Spyro during his journey to find his mother.
It could be Zamasu. Since Goku Black was Zamasu in Goku's body in the original story, perhaps a more powerful and enraged Zamasu could be the main antagonist. He might be jealous of the new fused form's power and seek to destroy it.
A powerful and greedy Pokémon collector could be the main antagonist. He might try to steal Ash's Pikachu or other strong Pokémon from them. He would constantly be one step ahead, setting up traps and obstacles for Ash and his sister during their travels.
It could be a member of Naruto's family who is fueling the neglect. Maybe an older relative who believes that the sister has more potential or is more worthy of attention and resources. This person could actively try to keep Naruto down.