Luteolin mitigates inflammatory organ injury by targeting XIAP to block PANoptosis and mitochondrial dysfunction

Introduction PANoptosis, an inflammatory cell death pathway that integrates pyroptosis, apoptosis, and necroptosis, contributes critically to the pathogenesis of inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). However, the molecular regulation of PANoptosis and its pharmacological intervention remain poorly defined. Objectives This study aimed to investigate the regulatory role of XIAP in PANoptosis and to evaluate the therapeutic potential of luteolin, a natural flavonoid, as a pharmacological inhibitor of PANoptosis. Methods Murine macrophage models were used to assess PANoptosis induction and inhibition. Structural and biochemical approaches were applied to determine the interaction between luteolin and XIAP. Mitochondrial function, ROS accumulation, oxidized mitochondrial DNA, and z-DNA generation were examined, while autophagy was evaluated as a modulatory mechanism. Therapeutic efficacy was further validated in a poly(I:C)/LPS-induced HLH mouse model. Results XIAP was identified as an essential component of the PANoptosome complex, and its knockdown abolished PANoptosis formation. Luteolin directly bound to XIAP, destabilized its structure, and disrupted its interaction with PANoptosome, thereby blocking PANoptosome assembly. Luteolin preserved mitochondrial integrity, reduced ROS accumulation, and inhibited the generation of oxidized mtDNA and z-DNA. Importantly, luteolin enhanced autophagic clearance of damaged mitochondria by relieving XIAP-mediated suppression of autophagy. In vivo, luteolin treatment significantly attenuated systemic inflammation, protected organ function, and improved survival in HLH mice, effects associated with diminished PANoptosome formation and reduced z-DNA accumulation. Conclusions This study establishes XIAP as a central regulator of PANoptosis and demonstrates luteolin as a natural inhibitor targeting XIAP to block PANoptosome assembly and mitochondrial dysfunction. These findings provide a novel pharmacological strategy for treating PANoptosis-driven inflammatory diseases.