Sea nettle jellyfish venom targets proteoglycans to cause cell death and pain

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.