Strato Incendus said:
What, if anything, can realistically go wrong on an interstellar journey?
The same things that can go wrong anywhere else.
Everything.
Strato Incendus said:
The problem is that all of these challenges are so big that, if a ship cannot handle them, there’s no point in it even leaving the solar system.
When it comes to airplanes, ships, spacecraft , etc, disasters don't usually happen because people knowingly design things that can't handle tough challenges, they usually happen because people
thought that what they were building could handle the situation, but it couldn't.
Some component or system going on the fritz halfway through a multi-generational voyage through space isn't bad storytelling or handwaving, it's an entirely plausible situation that is similar to those which have plagued engineers and production companies throughout all of history. Things break. Often unexpectedly and when they shouldn't. The bigger, more powerful, or more complicated the thing, the bigger the problems (and often fireworks) when it breaks.
Strato Incendus said:
Even internal failures of the ship aren’t that easy to create. A hull breach, as it seems to happen quite frequently in Star Trek (or even more vividly in one episode of The Expanse), shouldn’t happen too easily, either: Not just because even minor collisions with dust speckles have to be avoided anyway; but also because the ship hull will have to be thick enough to shield everyone inside against radiation.
Then you have a boring ship, a lack of imagination, and/or an unwillingness to handwave away something that should be mostly unimportant in its details. Unless you are writing a story about an engineer investigating the details of how some component failed, and those details are actually very important to the story, then just blow open a hole in the ship, start a fire somewhere, have a group of teens go on a rampage, make the captain go crazy, or use any of a million other possibilities.
Strato Incendus said:
Finally, deliberate human sabotage is also hard to justify
Human sabotage is quite possibly the easiest thing to justify, because it doesn't have to make logical sense or require that you make a leak-proof case about why some critical system blew up at an inopportune moment. I can literally start a story with this premise with no problem. I'll do it right now.
Bob turned over, grabbed his wrench from under his pillow, and hit his alarm clock as hard as he could. Yawning, he got up, wrench in hand, and went to his clothes locker in the corner of the room where he dressed. Afterwards he brushed his teeth, tossing his wrench into the air over and over again with one hand while he brushed with the other. He spit, rinsed, and then smiled into the mirror above the sink.
"Today's the day." He said quietly. "Today's the day they all meet the real me."
Bob chuckled and then turned around and walked to the door. He hit the open button and would, in a very short time from now, walk into the pages of history as the Wrenching Wreckman of Wickerson Way. Wickerson Way being the name of the ship he was about to empty of all life. Happy wrenching, Bob!
Granted, this particular style probably isn't what you're going for, but I'm using it to illustrate that there need not be any real justification at all.
"And then someone blew themselves and half our food out of an airlock" is a perfectly good way of introducing a problem for your cast of characters to overcome.
The fact that people often do awful, terrible, illogical things is so well understood that your audience rarely requires an explanation as to why.