Maybe there are corrupt local officials or businessmen in the fanfiction. They want to demolish the red light district to build something else more profitable, not caring about the people who live and work there. So Naruto has to protect the district from these people who are trying to force them out.
The plot might involve Naruto learning that there are innocent people in the red light district who are being exploited in ways other than the obvious. He could start by befriending some of the residents, like the bar owners or the dancers. As he gets more involved, he realizes that there are powerful people trying to use the district for their own gain. Naruto then has to use his Rasengan and other jutsu to fight off these villains and protect the district and its people.
Maybe there are powerful dark sorcerers. These sorcerers could be trying to capture Naruto for their own evil purposes, like using his power to open a portal to a dark dimension or something, and Kurama has to protect him from them.
Perhaps there are some shinobi within the village who are jealous of Naruto's potential. They might try to harm Naruto in secret, and Hiruzen has to be vigilant against them. These shinobi could be from clans that have rivalries with the Uzumaki or those who just don't want a new powerful force emerging in the village.
Another possibility is a new and powerful enemy from a neighboring village. This enemy might view fem Naruto as a symbol of the strength of her village and wants to take her out to weaken the village. Shikamaru then has to protect her from this external threat.
It could be Orochimaru. He's always been after power and Naruto's unique abilities would be very appealing to him. So the fem Kyuubi would have to constantly be on guard against Orochimaru's schemes.
It could be a new dark wizard who wants to make a name for himself. He sees Hogsmeade as an easy target to show his power. He starts by causing small disruptions like making objects in the shops move on their own and then escalates to more dangerous attacks that Harry has to stop.
Maybe some of Tony's business rivals who have access to advanced technology. They could be jealous of Tony's relationship with Ultron and try to harm him. They might hire mercenaries or develop their own weapons to go after Tony. In this fanfiction, these rivals would be the main antagonists as they constantly try to break through Ultron's protection of Tony.
In many cases, the main antagonists can be other Slytherins who still hold grudges against Harry or are loyal to the pure - blood supremacist ideology. They might see Harry as a threat to their way of life. Also, some Death Eaters can be antagonists. They target Harry because of his role in Voldemort's downfall and would stop at nothing to get to him.
It could be the Fire Nation remnants who still hold grudges against the airbenders. They might be trying to finish what they started years ago.
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.