Saisei's death. Especially since it's also probably the first time we see Akira show real emotion or regret.
The real Kubira has a sad story as well. He sold himself into the service of the Former Crimson King when he struck a deal to save his daughter, Anju. He was turned into one of the Berserkers - essentially biological weapons - and has to keep his distance from his daughter so he doesn't kill her. Akira decides not to kill him after defeating him, but because Kubira has broken his contract with the Taishiro, he dies anyway.
Hishigi dying as we learn just how far he's gone to try to save the Mibu clan and his friend, and his speech to Fubuki just before dying in his arms.
Del Rey English translation of the Final Speech in question:
Hishigi: It seems my heart still works... even after losing yours, this should enable you to live on....
Hishigi: A-and when... did I ever need your thanks...? You pompous fool.... I-I have never claimed... to be accompanying you.... Y-you have no crime to feel guilty of.... I chose... my own way. I picked the place I would survive... until death finally found me....
Muramasa: (flashback) Hishigi, look after Fubuki for me.
Hishigi: I'm sorry, Muramasa. I could not keep my promise....
Hishigi: Thank you, Fubuki... I hope you can find the heart... to forgive me... for leaving you all alone....
Fubuki trying to keep Hishigi alive. He's been in denial for decades about the fact that Hishigi is dying, and there is nothing he can do about it. In their final battle, when he realizes that Hishigi is planning to sacrifice himself for a chance to save Fubuki's life, Fubuki starts screaming for Hishigi to stay away. It's heartbreaking, and easily the most frantic and emotional we ever see Fubuki. Not to mention the look on his face as Hishigi dies in his arms, and the dust that used to be Fubuki's best friend falls through his fingers and floats away on the wind.
Akari's entire history with Hishigi. He was the one who took her in as a child, and the memories he gives her before he dies reveal that she clearly was very important to him. He even looks like he might be laughing in one of those panels. And in his final battle, after all of the Devil Eyes have been destroyed - the one on Akari's hand as well as the ones that have been keeping Hishigi alive - they get a couple of scenes that are just devastating.
First she tries to save him after the Devil Eyes fail. He tries to convince her that he's not worth it and that she should just let him die, but she won't because she doesn't want to lose anyone else. Her line to him, "As long as someone will mourn your passing, you aren't allowed to choose death for yourself," hits especially close to home for anyone who is living with mental illness or has lost someone to suicide.
She breaks down again once she has lived the memories he left to her as he died, which reveal how desperately he tried to save the Mibu, how he broke after contracting the disease himself, and that he truly considered her a trusted friend.
Fubuki's final scene. He has thrown himself onto Shinrei's sword in atonement for the crimes he and Hishigi committed in attempting the Mibu Reconstruction Project. He has collapsed on the ground and is very near death when Tokito shows up, having just regained the memory that Fubuki is her father. When she calls him her father, Fubuki reveals why he gave her those Fake Memories — he sees himself as a monster, and wanted her to live as the child of Muramasa, "the saint". Then the Former Crimson King tries to kill Tokito, and Fubuki finds the strength to throw himself in front of the bolt to save her.
Kyo ordering the others to run as he has been horribly wounded and the Crimson Tower is collapsing around him. He's clearly in agony, and he might even be scared. But he holds it together long enough to yell at Kyoshiro to get Yuya out.