Prey-specific toxins provide broad venom activity in cephalopods

Abstract Cephalopods are among the ocean’s most sophisticated predators that use camouflage, complex behaviors, and venom to subdue a wide range of prey. However, the functional role of venom across diverse prey remains poorly understood, particularly whether cephalopods deploy venom to capture fish. Through comprehensive transcriptomic profiling of venom glands, we identify toxins with molecular signatures of prey-specific adaptation, including a previously unrecognized family of peptide toxins, octotensins, that evolved through convergent evolution to mimic the vertebrate hormone neurotensin. Functional assays and cryo-electron microscopy demonstrate that octotensins potently activate fish and human neurotensin receptor 1, engage this target in a near-identical manner to the chordate hormone, and induce acute hypotension in rodents. Together, our findings demonstrate that cephalopods achieve broad venom activity through phylum-specific toxins, including those targeting fish, revealing an evolutionary strategy by which generalist predators can capture phylogenetically diverse prey. One-Sentence Summary Cephalopod venom comprises prey-specific toxins, including neurotensin-mimicking peptides that target fish.