Ere when she finds out that Report is still alive.
A dying Sir Romra offering his helmet to Naharrud, so the latter could finally read all those books like he wanted.
Regnis's death. Oh God.
"My song... and my love... don't forget them..."
Made even worse by the previous pages, where Gabe repeated tries to use his powers to heal her, repeatedly getting hit by his own Lightning but not giving up, only to fail in the end.
Ere (again) in the "Worst Case Scenario", only this time she killed Report with her own hands.
Even more heartbreaking when she and Neeuq make their way out of the factory and the normally graceful and competent Ere is completely disoriented, stumbling into every obstacle along the way but still refusing to let Neeuq help her carry Report's body.
Also, when she is dismembered and Left for Dead by Dab Gib and uses her only remaining hand to crawl over to Report's body and hug it before dying herself.
"I... I don't drink tea very often." Gets me every time.
A bit earlier than the rest of these, but I think everyone remembers this line
Gib: I used to think the stars were worth looking at... not anymore.
As much as the fans hated him, the end of G'nignah was so savagely brutal that even hardened haters of the character felt bad for him.
G'nignah: Heh... C-come on, guys... We all knew... this was... coming...
The reason Yug cannot use Tropes the way others can is finally revealed in the OREZ arc. he Took The Bullet for Dab from the barrel of Nightmare Fuel that corrupted Dab in the first place. Turns out that blocks off his wiki channels, meaning he is unable to manifest Tropes properly. Even worse, Dab was still infected, meaning his younger brother's near death and life-crippling debilitation ultimately failed to impact anything. Worse still, Yug is slowly succumbing to The Virus that he's been hiding from everyone.
After Report's memory loss, Ere bursts into tears and begs him to come back, whereas Retrope just buries her face in her arms.
Angelica sacrificing herself to save Susano'o from his own mind. The worst part is that, since Angelica died before her time, Fayejin performs a Face–Heel Turn and becomes The Dragon.
However, it also leads to a mildly Heartwarming moment, when Report gets all his memories back and Ere and Retrope come back to W.I.K.I..
In the Western Zodiac arc, Ere taking the Apple of Light from the Star Tree sets off a chain of events that have multiple Tearjerking moments.
The most memorable is Capricorn's death. Namely, he killed himself by jumping into the Sea of Tears. Woah.
The W.I.K.I. agents' reaction to finding out Agni killed Odin, since Odin was a good friend throughout the series.
The Inversion can be considered this. According to Reginald, several Inverters have had to disappear off the face of the Earth so they wouldn't hurt friends or family, and the few who are still known have a bad rep because of the Inversion. To make matters worse, Inverters have to use the Inversion to tap into their powers, and must constantly remind themselves who they are lest the Inversion consume them.
And the icing on the cake? In a cruel twist of irony, Reginald hid this information from Minnie so she wouldn't have to worry about it. If he had told her about the Inversion, she probably wouldn't've died at his own, Inverted hands.