Perhaps an old enemy from Naruto's past that was thought to be defeated has resurfaced. This enemy might have targeted Naruto's wife as a way to get revenge on Naruto for their previous defeats. They could be using her as a bait to lure Naruto into a trap.
It could be a rogue ninja who has a vendetta against Naruto. This ninja might see Naruto's son as a way to get back at Naruto for past defeats or slights.
A possible main antagonist in such a fanfic could be a dark entity that has possessed someone close to Naruto. This entity could be using the host's body to get close to Naruto and then attacks him, resulting in the loss of his arm. Naruto would then have to figure out not only how to deal with his injury but also how to save his friend from the dark entity's control.
It could be someone from the Naruto universe who doesn't like Naruto's newfound fascination with Aku. For example, Danzo might see Naruto's interest in Aku as a threat to the stability of the village and try to stop Naruto from further exploring Aku - related things. So, Danzo could be the main antagonist in this case.
The main antagonist could also be a new and unknown force from the Underworld. It could be a powerful spirit or entity that is spreading despair among the demigods. Percy tries to fight against it but finds it so difficult that he begins to lose hope in the face of this seemingly invincible foe.
It could be a dark wizard who has some connection to the sea. Maybe he wants to stop Harry from reaching a certain destination in the sea.
Perhaps an older, forgotten enemy of the Lost Boys could resurface. Maybe someone from their past in Neverland who they thought was defeated but has now returned with a vengeance. This could be a character who was once a Lost Boy himself but turned bad due to some dark influence in Neverland.
It could be a dark wizard who has also found his way into space. This wizard might be using the new environment to develop even more powerful and dangerous dark magic.
It could be Captain Hook. Since Harry Potter has magic, Hook might see him as a huge threat to his plans in Neverland. He would try to capture Harry and use his magic for his own evil purposes, or simply get rid of him to maintain his control over the island.
A group of rogue ninja who are hunting nekoshou for their special powers could be the main antagonists. They see Naruto's newfound connection with the nekoshou as a threat and try to eliminate him and the nekoshou he is protecting.
It could be a corrupt ninja from within the village who wants Naruto out of the way. Maybe someone jealous of Naruto's popularity and power, so they frame him and get him sent to prison. This antagonist would then try to keep Naruto in prison by any means necessary.