As a brief introduction, please note that I've labelled the sections of this guide according to their relevant years, and that there will be spoilers... obviously.

And, of course, remember that this is just my personal interpretation, not absolute fact. Feel free to correct or challenge my analysis in the comments!

For some foundational context, we play as a young Lorelei Weiss, wandering through a surreal hotel inhabited by present-day (elderly) Lorelei’s memories–This may cause some confusion, as the game commonly suggests the hotel is of 1963 while being filled with 2014 documents (such as Lorelei’s medical records). Thankfully, the setting is cleared up by the game's ending sequence.

Though Lorenzo and Renate have physical presence throughout the game, the following is crucial: they’re actually fictional characters from Nero Renzo’s story The Third Eye, set in 1847. In the story (which can be pieced together using the script pages found in room 1963), Renate undergoes a disturbing transformation much similar to that of Renzo’s in the game’s final cutscene.

Panicked, Lorenzo backs away before shoving Renate out of an upper floor window, killing her.

With that in mind, let’s cover what really happened. Be sure to keep in mind that Lorelei is not Renate, and Renzo is not Lorenzo. Though, of course, these characters have strong, intentional parallels.

In Renzo’s biography, it's stated that he goes to an art show and calls Lorelei a "woman with laser eyes," eventually contracting her to make an art piece for him--the OCU-3 supercomputer.

This unique art piece would serve as an interactive element of the Third Eye project. However, Renzo's request was (to some extent) a pretext. While he did want the computer to be made, his real goal was to use his own death to create the ultimate "artwork," meshing reality with the fictional story he had written to create striking parallels.

After some time working on said project at the hotel, Lorelei is frightened by his eccentric and erratic behavior–actions we repeatedly see in the game’s flashbacks and script pages, and alluded to through Robert Sidney's 1962 letter of warning.

To parallel Renate in The Third Eye, Renzo blinds himself and chases Lorelei with a revolver, shooting in random directions. With Lorelei unable to escape (as Renzo locked the hotel doors), she is forced to play Lorenzo's fictional role--Lorelei pushes Renzo out of one of the hotel's upper windows, killing him.

Through this, Renzo accomplishes his artistic goals, creating a piece that requires no audience--one that only the performers could appreciate (an artistic idea regularly alluded to or directly stated throughout Renzo's many interviews).

Though the police interrogate Lorelei, they come to the conclusion that Renzo’s death was a suicide. Unfortunately, Lorelei’s trauma from her part in Renzo’s death prevents her from moving on with her life. Rather, she constantly relives memories of the event over and over again--hence the simultaneously young and old protagonist. Her entire life is reduced to a singular mistake, and she withdraws from not only the public eye, but the entire art world. In fact, one of the newspaper articles about her mysterious career mentions that she became popular for her involvement in the tragedy rather than her art (though the associated police records are full of redacted and nonspecific information).

Furthermore, in the cellar’s jail cell, Renzo states that he's been trapped by Lorelei for 51 years--exactly the amount of time from 1963 (when the incident occurred) and 2014 (the present year).

As an aside, it should be noted that Lorelei and Renzo were not lovers, despite Renzo's flirty nature. In fact, during the dance scene trailing the piano puzzle’s solution, the following conversation can be had, should Lorelei say they are not interested in flirting with Renzo:

R: "A dog can waltz with cats, but still only enjoy the cha-cha of another dog."
L: "Ah, I didn't know."
R: "You don't read the gossip magazines, then. It does you great honor."

With this in mind, one can assume that Renzo is gay, and sees his relationship with Lorelei as that of a muse. Furthermore, Lorelei is never depicted as being in a relationship, and she finds the Ace of Spades in the fortune teller's tent--with an item description discussing its symbolism of asexuality.

In the context of the game's ending, these details make it clear that Lorelei is making peace with her past as a whole, not the death of someone she loved.

Lorelei’s entire existence revolves around three monumental years in her life: 1847 and 1963, in which Renzo’s ironic defenestration is entangled, and 2014, the current and final year of her life (with her eyes closed by Renzo’s ghost just as the credits roll).

Of course, this isn’t an in-depth analysis--it's a personal interpretation--but it should hopefully answer any questions regarding the game’s ending. It certainly helped me to piece my thoughts together!

Lastly, feel free to leave any thoughts, questions, or general feedback below--I'd love to read some different interpretations. And thank you to those in the comments who have already provided excellent insight and feedback!