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Sea nettle jellyfish cause millions of painful stings annually with little known about how their venom works and no rational treatments available. Here, we perform a systematic analysis of sea nettle venom/host interactions. The venom shows dose-dependent cytotoxic activity in human cells, and this can be blocked by dual inhibition of apoptosis and necroptosis. Using whole-genome CRISPR screening, we identified human genes and pathways that modify venom action. The top gene cluster identified regulates proteoglycan biosynthesis. We show that exogenous heparin, a drug used clinically as an anticoagulant, blocks venom cytotoxicity at a physiologically relevant dose. This effect was therapeutic, inhibiting venom even 1 hour after exposure. In vivo, heparin protected against acute spontaneous pain, thermal hyperalgesia, and mechanical allodynia induced by venom. This provides the exciting possibility of repurposing heparin, a safe, commercially available drug, as a prophylactic or therapeutic to reduce the impact of sea nettle stings.

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