What Malaise is
Malaise is the corruption mechanic that turns the highest difficulty tier into something structurally different rather than just numerically harder. It builds as you take hits, and it is cleared by the Health Flask — the wiki states that each flask use removes 150 points, which is three bars.
That single number reframes the whole tier: your flask stops being only a heal and becomes your Malaise management tool. Which is exactly why the flask upgrade line (Flask II, III, IV) is worth more at 5 BC than almost anything else you can buy.
When it turns on
The wiki lists Malaise as activated at the fifth Boss Cell — the Hell tier — together with the two things that tier is really for: the Astrolab and the Observatory.
Some player-facing guides also describe corrupted food appearing a tier earlier, so if you are at 4 BC and food behaves strangely, that is the same mechanic starting to bite.
The hidden cost: infected food
At higher tiers, some of the food found in levels is infected by Malaise. This is the part that catches players out, because food is normally the free, safe heal — the thing you eat when you do not want to spend a flask charge.
Once food can be corrupted, that fallback is gone. You cannot graze your way through a biome any more; every heal decision becomes a flask decision, and flask charges are exactly what the higher tiers have already been taking away.
How to play around it
Over-invest in the flask. Flask I is 5 cells and must come first; Flask II is 50, Flask III is 150 (needs 10 unlocks) and Flask IV is 300 (needs 25 unlocks). At 5 BC these are survival purchases, not luxuries.
Do not eat food blindly. If a food item looks off, it is. The 150-point flask clear is worth more than the risk.
Treat hits as a resource, not just damage. Below 5 BC a hit costs health. At 5 BC a hit also costs Malaise, and Malaise costs flask charges, which are already scarce. The compounding is what makes the tier hard.
Use the passage. The passage between biomes is where you can re-roll and upgrade gear and replenish health potions. At 5 BC it is also where you plan the next biome’s flask economy.
How this fits the rest of the tier
5 BC also removes the Collector from passages (his apprentice replaces him, with no functional difference), triples enemy cell drops, and adds the Astrolab leading to the true final boss. Malaise is the mechanic that makes all of that earnable rather than free.