Intrinsic apoptosis in nematodes: Evolutionary plasticity and biotechnological opportunities.

Intrinsic apoptosis is a form of programmed cell death that underpins development, tissue homeostasis and stress responses across Metazoa. In roundworms (nematodes), the pathway was first genetically defined in the free-living nematode Caenorhabditis elegans, yet how it has diversified and operates across the phylum Nematoda, encompassing parasites of humans and animals spanning clades IV, remains incompletely resolved. Here, we synthesise comparative genomic, structural and functional evidence to establish a framework for intrinsic apoptosis in nematodes. Although the core CED-9-CED-4-CED-3 module is broadly retained, regulatory wiring and developmental deployment remain largely uncharacterised beyond C. elegans. Unlike vertebrates, nematodes lack a canonical BAX/BAK-driven mitochondrial permeabilisation system, revealing what we term the "Nematode Apoptosis Paradox" - caspase activation in the absence of the mitochondrial amplification step central to vertebrate intrinsic apoptosis. This alternative regulatory configuration, coupled with structural divergence of nematode BCL-2-like proteins from their vertebrate homologues, suggests a distinctive evolutionary trajectory for apoptotic regulation in Nematoda. By integrating evolutionary cell biology with emerging structural and pharmacological insights, we define a conceptual framework for interrogating apoptosis across clades IV and evaluate its potential as a target for anthelmintic discovery.