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With the "death"s of Superman, Batman, & Phoenix all "reset" by later writers hoping to cash in, the only death in comics I recall being permanent was Gwen Stacy (& that's excluding her clones...).
So, what would be the effect of killing Lois, & having her stay dead? What would it take for the book's writer to do it? Pick any period. No imaginary stories--real continuity, really dead; no robots, aliens, or clones allowed.
I'd guess the only way to make it stick is for DC management to just be thoroughly sick of her, & possibly insane.