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 I-V, 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 I-V and evaluate its potential as a target for anthelmintic discovery.