A plot twist could be that the person who breaks Harry's heart has a secret identity. They could be a spy from an enemy group, but during their time with Harry, they actually fell in love too. However, their loyalty to their original group makes them break Harry's heart. Or perhaps the heartbreak is due to a time - traveling incident. Harry meets someone from the future who has to leave him in order to preserve the timeline. And also, it could be that the one who breaks Harry's heart is actually under a spell that makes them act out of character, and when the spell is broken, they try to come back to Harry but it's too late.
It could be Ginny. Maybe in the fanfiction, Ginny has some internal struggle that she hasn't shared with Harry. For example, she might feel overshadowed by Harry's fame and decides to break up with him to find her own identity. Another possibility is Hermione. If she realizes that her friendship with Harry is being compromised by her growing romantic feelings that she doesn't want to act on, she could break his heart to preserve their friendship. And then there's Luna. Luna might break Harry's heart if she discovers that their different worldviews are too much to overcome, even though they had a connection.
One possible reason could be unrequited love. Maybe Natsu has feelings for someone who doesn't feel the same way about him. This could lead to his heartbreak as he realizes that his love is not reciprocated.
Well, perhaps in the fanfiction, Ash is betrayed by a group of friends he trusted deeply. They might have used him to get access to some rare Pokémon or some important information, and then they turn their backs on him. This would be a huge heartbreak for Ash, who is always so loyal to his friends. Or it could be that he fails to achieve a major goal like winning a big Pokémon tournament due to some unfair circumstances, and he feels heartbroken as all his efforts seem to be in vain.
It could be that there is some misunderstanding between them. Say, Misty misinterprets something Ash does as him not caring about her anymore. Ash, being clueless about her misinterpretation, doesn't correct it in time. Then Misty distances herself from him, and Ash is left heartbroken when he finally realizes what has happened.
He might isolate himself at first. Natsu could withdraw from his friends and normal activities, needing time alone to process his pain. This is a common way for people, or in this case, characters, to deal with heartbreak.
It could slow him down. Ash might be so distraught that he doesn't focus well on training his Pokemon. His usual enthusiasm for battles and catching new Pokemon might wane, as his mind is preoccupied with his broken heart.
Well, it could be due to the failure to protect the village. Naruto has always been about protecting Konoha. If something really bad happened, like a major attack that he couldn't prevent and many lives were lost, he might feel so much guilt and heartbreak that he decides to leave. He would feel like he failed his purpose.
A new, powerful villain could be the cause. This villain might target Ash's Pokémon and manage to steal them all away. Ash would be heartbroken not only because he lost his Pokémon but also because he feels he has failed to protect them.
A theme that often pops up is the idea of growth. Heartbreak can be a catalyst for Natsu to grow as a character. He might become more empathetic or learn to be more cautious in relationships. Also, the theme of forgiveness can be present. He may have to forgive the person who caused his heartbreak to move on.