Evodiamine protects against lung ischemia-reperfusion injury by attenuating SYK-associated TLR4/NLRP3 inflammasome activation and ferroptosis-related injury signatures.

Lung ischemia-reperfusion (I/R) injury is a major driver of acute lung dysfunction after procedures such as lung transplantation, yet effective pharmacological strategies remain limited. We evaluated whether evodiamine (EVO) mitigates lung I/R injury and explored potential mechanisms. Male C57BL/6 mice underwent left pulmonary hilar occlusion (60 min) followed by reperfusion (120 min) and received EVO, the SYK inhibitor BAY61-3606, or the combination. Compared with I/R alone, treatment reduced histopathological damage, inflammatory cytokine expression, apoptosis, and ferroptosis-associated marker changes (iron overload, PTGS2 induction, and loss of GPX4/SLC7A11). EVO was associated with decreased activation of the SYK/TLR4/NLRP3 inflammasome axis, and BAY61-3606 recapitulated several protective effects. Because the mechanistic inference is based on pharmacological inhibition, these findings support-rather than definitively prove-SYK-linked TLR4/NLRP3 signaling as an important node in EVO-mediated protection. Together, the data suggest that evodiamine alleviates acute lung I/R injury in part by restraining inflammatory signaling and modulating ferroptosis-related markers.