There could be a group of rogue ninjas who see Sakura as a threat to their plans. If she becomes Hokage, she will surely enforce the rules more strictly and disrupt their illegal activities. They would try to stop her by any means necessary, including assassinations attempts and framing her for crimes she didn't commit. Also, some of the more traditionalist ninja in the village who believe only a male from a certain clan should be Hokage could act as antagonists by trying to block her progress at every turn.
One possible main antagonist could be a shinobi from another village who fears Sakura's potential as Hokage. This shinobi might try to undermine her by causing chaos in her village or spreading false rumors about her abilities. Another could be someone within her own village who has a long - standing grudge against her or her family and doesn't want to see her in a position of power.
Well, one possible plot could be that Sakura works extremely hard in her medical ninjutsu and combat skills. She might start taking on more leadership roles in the village during times of crisis. For example, when the village is short on resources or facing a new enemy threat, Sakura steps up. She uses her intelligence to come up with strategies and her strength to inspire others. Along the way, she has to deal with those who doubt her ability to be Hokage because she's not from one of the traditional 'power' clans. But through her determination and the respect she earns from her peers and the villagers, she finally becomes Hokage.
Another possibility is that a new, unknown group from outside the village emerges as the antagonists. They see Naruto as a threat to their own plans for domination or chaos, and they target the village under his leadership. This group could have unique powers and abilities that Naruto and the villagers have never faced before, making it a real test for Naruto as the Hokage.
Another possibility is a rival clan. They might target Sakura specifically because she is seen as a rising star within her clan and they want to undermine her clan's strength. For instance, they could try to kidnap her or spread false rumors about her to create discord within her clan.
A group of corrupt politicians within the village itself could be the main antagonists. They might be secretly plotting to undermine Naruto's authority as the 5th Hokage in order to gain more power for themselves. They could be making deals with other villages or ninja groups that are not in the best interest of Konoha, and Naruto has to expose and stop their schemes.
It could be some of the old enemies who were thought to be defeated but managed to come back. For example, Orochimaru's former followers who still hold a grudge against Naruto and Konoha. They might see Naruto's retirement as an opportunity to strike.
Perhaps a secret organization that had been hidden for centuries and didn't want the new order that Konoha represented. They could have dark magic or forbidden jutsu at their disposal and use it to try and stop the First Hokage from achieving his goals. This would force the First Hokage to not only rely on his physical strength and known ninja techniques but also to find ways to counter the unknown and mysterious powers of this secret organization.
It could be a group of rogue ninja who have a vendetta against Naruto. They might see his new status as a rogue as an opportunity to take him down. Maybe they were once defeated by Naruto when he was in the village, and now they want revenge. Also, there could be some hidden shinobi clans within the village who oppose Naruto's new path and try to stop him for their own reasons, like protecting the village's reputation or their own power within the village.
The other ninja clans in Konoha could be his allies as well. Since Baruto has shown his strength and determination, clans like the Uchiha (if they still exist in the fanfic) and the Hyuga might support him. They would see him as a unifying figure who can lead Konoha to a better future and protect their interests within the village.
Another possible antagonist could be a jealous relative. For example, a cousin who believes they should be the heir instead of Sakura. This relative could spread false rumors about her, or try to sabotage her efforts to prove her royalty in more subtle ways, like stealing important documents or artifacts related to her claim to the throne.
Sakura would be the main character as it's about her becoming the sixth Hokage. Naruto and Sasuke might also be important characters as they are her friends and have a big influence on the Naruto world.