Cytokine Storm Induction Linked to Multi‐Organ Failure in Fatal Jellyfish Stings

Abstract Fatal jellyfish stings often cause multi‐organ failure. Until now, these fatal outcomes are attributed to the direct toxic effects of the venom. Here, a mouse model of delayed jellyfish envenomation syndrome (DJES) is established and showed that venom from Nemopilema nomurai jellyfish can trigger a deadly cytokine storm – a severe inflammatory reaction. Mice injected with the venom displayed acute multi‐organ failure and significant upregulation of over 20 pro‐inflammatory cytokines (including IL‐6, TNF‐α, CXCL2, and CCL4) in the heart, liver, and kidneys. Transcriptomic analyses identified NF‐κB p65 subunit activation as central to the cytokine storm induction. Knockdown of p65 in macrophages reduced cytokine production and improved cell viability. Treatment with dexamethasone, an NF‐κB inhibitor, effectively suppressed the cytokine storm, mitigated organ damage, and increased survival rates in mice. The findings present new insights to treat fatal jellyfish stings.