Jellyfish stings
are a major threat to human beings in coastal
areas of the world. Each year, hundreds of thousands of victims are
stung by venomous jellyfish. Nemopilema nomurai is
a dangerous species with a large number of victims including many
deaths. N. nomurai venom is a complex cocktail that
is rich in proteins and peptides, and it is secreted by nematocysts
for prey or defense. Previous studies have identified hundreds of
toxins in the venom of N. nomurai; however, it is
unclear which toxin(s) is responsible for lethality. Herein, we isolated
the lethal fraction (NnLF) from N. nomurai venom
with multiple chromatography. NnLF showed strong lethality to mice,
and the toxicology results were consistent with the clinical symptoms
of dead patients after N. nomurai sting, which indicated
that NnLF contained the key lethal toxins in the venom. Subsequently,
proteomic analysis was performed to identify the toxins in NnLF, and
a total of 13 toxin homologues were identified, including phospholipase,
potassium channel inhibitor, hemolysin, thrombin, etc. Moreover, in
vitro toxicity assays further verified the phospholipase A2 and hemolytic activity of NnLF. These results revealed that cell
membrane-targeted toxins, including channel-forming toxins, potassium
channel inhibitors, and especially phospholipases, played very important
roles in the lethality of N. nomurai sting. Moreover,
blood toxins such as thrombin-like toxin and hemolysins might be synergistically
involved in lethality. These findings advance the understanding of
lethality caused by N. nomurai sting and will be
significant for the development of drugs to treat this jellyfish sting
in the future.