Sepsis,a life-threatening inflammatory disorder characterized by multiorgan failure,arises from a dysregulated immune response to infection.Modulating macrophage polarization has emerged as a promising strategy to con...Sepsis,a life-threatening inflammatory disorder characterized by multiorgan failure,arises from a dysregulated immune response to infection.Modulating macrophage polarization has emerged as a promising strategy to control sepsis-associated inflammation.The endogenous metabolite itaconate has shown anti-inflammatory potential by suppressing the stimulator of interferon genes(STING)pathway,but its efficacy is inhibited by hyperactive glycolysis,which sustains macrophage overactivation.Here,we revealed a critical crosstalk between the itaconate-STING axis and glycolysis in macrophage-mediated inflammation.Building on this interplay,we developed a novel nanoparticle LDO(lonidamine disulfide 4-octyl-itaconate),a self-assembled metabolic regulator integrating an itaconate derivative with the glycolysis inhibitor Lonidamine.By concurrently targeting glycolysis and STING pathways,LDO reprograms macrophages to restore balanced polarization.In sepsis models,LDO effectively attenuates CCL2-driven cytokine storms,alleviates acute lung injury,and significantly enhances survival via metabolic reprogramming.This study offers a cytokine-regulatory strategy rooted in immunometabolism,providing a foundation for the translational development of immune metabolite-based sepsis therapies.展开更多
基金supported by the National Natural Science Foundation of China(82173682)the Shenzhen Science and Technology Program(JCYJ20240813150807010)+3 种基金the Innovation Capability Support Program of Shaanxi(2021KJXX-92)he Shaanxi Province Key Industry Innovation Chain Project(2023-ZDLSF-59)the Shaanxi Youth Rising Stars in Science and Technology(2024ZC-KJXX-119)the Key Research and Development Program of Shaanxi Province(2022SF-374).
文摘Sepsis,a life-threatening inflammatory disorder characterized by multiorgan failure,arises from a dysregulated immune response to infection.Modulating macrophage polarization has emerged as a promising strategy to control sepsis-associated inflammation.The endogenous metabolite itaconate has shown anti-inflammatory potential by suppressing the stimulator of interferon genes(STING)pathway,but its efficacy is inhibited by hyperactive glycolysis,which sustains macrophage overactivation.Here,we revealed a critical crosstalk between the itaconate-STING axis and glycolysis in macrophage-mediated inflammation.Building on this interplay,we developed a novel nanoparticle LDO(lonidamine disulfide 4-octyl-itaconate),a self-assembled metabolic regulator integrating an itaconate derivative with the glycolysis inhibitor Lonidamine.By concurrently targeting glycolysis and STING pathways,LDO reprograms macrophages to restore balanced polarization.In sepsis models,LDO effectively attenuates CCL2-driven cytokine storms,alleviates acute lung injury,and significantly enhances survival via metabolic reprogramming.This study offers a cytokine-regulatory strategy rooted in immunometabolism,providing a foundation for the translational development of immune metabolite-based sepsis therapies.
