Zebrafish lack canonical necroptosis despite retaining functional RIPK3

Zebrafish lack canonical necroptosis because they lack MLKL, even though they retain functional RIPK3, as shown by caspase-8–dependent necroptosis tests and RIPK3 overexpression.

• Why it matters: Canonical necroptosis is a proposed backup antimicrobial defense, but species lacking MLKL are predicted to be unable to execute it, leaving zebrafish biology uncertain.
• What they did: The study experimentally tested the prediction using zebrafish with caspase-8 deficiency (viable through adulthood) and compared with mouse embryonic lethality unless RIPK3 or MLKL was inhibited; Ripk3 overexpression did not induce death in caspase-8–deficient embryos.
• The result: These findings support zebrafish as a model to study RIPK3-linked, non-canonical necrosis and extrinsic apoptosis biology in disease contexts without canonical necroptotic execution.

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