摘要Necroptosis,a necrotic form of regulated cell death,plays a crucial role in various tissues and disorders,including sepsis.This process occurs primarily through a caspase-independent mechanism mediated by receptor-interacting protein kinase 1(RIPK1),RIPK3,and mixed lin-eage kinase domain-like(MLKL).Necroptosis-related diseases frequently manifest with ex-cessive inflammatory responses.Corilagin,a gallotannin exhibiting potent anti-inflammatory and anti-oxidant properties,has received increasing attention.However,its effects on necrop-tosis and associated disorders remain unexplored.In this study,we utilize a surface plasmon resonance-liquid chromatography-tandem mass spectrometry(SPR-LCMS/MS)screening ap-proach to identify corilagin's target proteins and demonstrate its binding to necroptosis-re-lated proteins.In vitro,corilagin inhibits necroptosis induced by either tuberculosis,tumor necrosis factor-α(TNF-α),LCL-161,and inhibitor(IDN-6556)(TSI)(tumor necrosis TNF-αcombined with LCL-161(a Smac mimic)and pan-caspase inhibitor IDN-6556),or lipopolysac-charide(LPS)with IDN-6556.Additionally,it suppresses the phosphorylation of MLKL,RIPK1,and RIPK3,while preventing necrosome formation during necroptotic induction.Cori-lagin also mitigates the TSI-induced reduction in mitochondrial membrane potential,a char-acteristic of necroptosis-associated mitochondrial dysfunction and the generation of mito-chondrial reactive oxygen species(mtROS).In a mouse model of sepsis associated with nec-roptosis,corilagin administration reduces the severity of LPS-induced acute lung injury,cor-relating with decreased MLKL phosphorylation in lung tissues.These results indicate that cor-ilagin attenuates RIPK1/RIPK3/MLKL signaling,potentially through reducing mtROS produc-tion,thereby inhibiting necroptosis and offering protection against LPS-induced acute lung in-jury.