Magnesium protects against sepsis by blocking gasdermin D N-terminal-induced pyroptosis

Hypomagnesemia is a significant risk factor for critically ill patients to develop sepsis, a life-threatening disease with a mortality rate over 25%. Our clinic data analysis showed that hypomagnesemia is associated with a decreased monocyte count in septic patients. At the cellular level, we found that Mg²⁺ inhibits pyroptosis. Specifically, Mg²⁺ limits the oligomerization and membrane localization of gasdermin D N-terminal (GSDMD-NT) upon the activation of either the canonical or noncanonical pyroptotic pathway. Mechanistically, we demonstrated that Ca²⁺ influx is a prerequisite for the function of GSDMD-NT. Mg²⁺ blocks Ca²⁺ influx by inhibiting the ATP-gated Ca²⁺ channel P2X7, thereby impeding the function of GSDMD-NT and inhibiting lipopolysaccharide (LPS)-induced noncanonical pyroptosis. Furthermore, Mg²⁺ administration protects mice from LPS-induced lethal septic shock. Together, our data reveal the underlying mechanism of how Mg²⁺ inhibits pyroptosis and suggest potential clinic applications of magnesium supplementation for sepsis prevention and treatment.