Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury.

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Multiple organ dysfunction syndrome (MODS) is the major cause of mortality of patients in intensive care units. The elusive mechanisms of tissue damage in MODS and limited therapeutic options encourage us to seek effective therapies to MODS. PANoptosis has recently been proven to be the key player in both heat stress and sepsis-mediated MODS. Therefore, we initially investigated the role of gasdermin D (GSDMD) in heat stress and sepsis-induced MODS. We found that GSDMD deficiency attenuates heat stress or sepsis mediated cell death, tissue inflammation and severe multiple organ injury (MOI). Next, we screened out and proved that JX06 effectively inhibited GSDMD-NT mediated cell death, by covalently modifying the Cys39/192 residue in GSDMD, inhibiting the accumulation of GSDMD-NT and pore formation in cell membrane. In vivo, JX06 administration attenuated heat stress and sepsis-mediated cell death, inflammation, MODS and animal mortality via suppressing GSDMD-mediated PANoptosis. Overall, our results indicated that GSDMD is critical for MODS by executing PANoptosis; administrating its inhibitor, JX06, effectively suppresses MODS by inhibiting PANoptosis, and suggesting that JX06 would be an effective drug candidate for MODS and related death.