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.
His own mentor could be the cause. Suppose his mentor, who he looked up to, tells him that he doesn't have what it takes to be a great Pokémon trainer. This would break Ash's heart as he has always strived to live up to his mentor's expectations.
Gary could also be the one to cause Ash's heartbreak. Maybe Gary outshines Ash in a big Pokemon battle and then mocks him for it. This could make Ash feel like a failure and break his heart. Gary has always been a bit of a rival to Ash, so this kind of situation is plausible in fanfiction.
It could be Annabeth. Maybe they had a huge fight over something important, like the future of their relationship or a difference in their values regarding their demigod duties. And this fight led to Annabeth leaving Percy, which broke his heart.
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.
Another possibility is that the Pokemon themselves could be the cause, in an unexpected way. For example, if one of Satoshi's Pokemon gets seriously ill and needs to be left in a far - away place for treatment. Satoshi decides to stay with the Pokemon, but Haruka has to continue her journey. This difficult decision could lead to heartbreak for both of them.
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.
Another character could be Kakashi. Maybe he has to make a tough decision that goes against Fem Naruto's wishes. For example, not allowing her to go on a dangerous mission she really wants to. This could make Fem Naruto feel betrayed and heartbroken, as Kakashi is a respected figure in her life.
There's also a chance that an old enemy from Ash's past resurfaces. This enemy, who has a long - standing grudge against Ash, could find a way to use Ash's Pokemon to get revenge. They might have developed new techniques or powers over time that allow them to influence the Pokemon's loyalty.
It could be his arch - enemy. For instance, the Joker might play a cruel trick on Nightwing that makes him lose someone he cares about deeply, thus causing his heartbreak.
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.
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.