Maybe there's a Pokémon that has been corrupted by dark energy. This Pokémon is extremely powerful and has a grudge against humans. It sees Ash and his sister as representatives of the human race and constantly attacks them. It's not just a simple battle, as the Pokémon is intelligent and uses its knowledge of the environment to ambush them at every turn, making it a very difficult antagonist to deal with.
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 an organization that believes in using Pokémon for evil purposes, like forcing them to fight in cruel and illegal battles. They see Ash and his sister as a threat to their operations because they promote a more ethical and kind way of treating Pokémon. So they do everything they can to stop them, from sending out their own tough trainers to sabotaging their journey.
It could be a powerful and jealous trainer who wants to take Ash's place. This trainer might use dark magic or some underhanded tactics to make Ash's Pokemon abandon him so that he can swoop in and claim them for his own.
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.
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.
It could be a jealous rival trainer who mocks Ash for wearing a dress and tries to use it as a way to undermine his confidence and stop him from competing in Pokemon battles.
It could be a jealous wizard who feels that Harry and his sister are getting too much attention in the wizarding world. This wizard might try to undermine their achievements and even put them in danger.
Another option is a jealous individual from Sakura's own time who somehow manages to follow her into the past. This person is envious of Sakura and wants to take over her role in the past - time events. They would constantly try to undermine Sakura and take credit for her actions, causing a lot of trouble for her during her time - traveling adventure.
It could be a jealous ninja in the village. This person might see Naruto's sister as an easy target since Naruto is often preoccupied. They could spread rumors about her or try to make her life difficult at the ninja academy, taking advantage of Naruto's absence.
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 a dark wizard who is jealous of the Potter family's fame and power. He sees Lemon as an easy target to get to Harry and plans to use her to lure Harry into a trap.
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.