结核分枝杆菌IDH-PPARγ相互作用抑制GPX4驱动巨噬细胞铁下垂并维持持续感染
Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection.
摘要(中文译文)
结核分枝杆菌（M.tb）在感染过程中会主动重编程宿主的脂质代谢；然而，其潜在机制仍知之甚少。M.tb如何操纵巨噬细胞脂质代谢以诱导脂质过氧化和铁死亡从而维持细菌持续存在，仍是一个基本问题。本研究利用单细胞RNA测序和蛋白质组学，发现M.tb感染可显著上调巨噬细胞中的过氧化物酶体增殖物激活受体γ（PPARγ）。在机制上，M.tb异柠檬酸脱氢酶（IDH）与PPARγ相互作用并损害其蛋白酶体降解。PPARγ水平升高通过将NCOR/SMRT辅阻遏物复合物募集至Gpx4启动子而抑制谷胱甘肽过氧化物酶4（Gpx4）的表达，导致感染巨噬细胞中脂质过氧化和铁死亡增加。在小鼠中，PPARγ敲除或药理学抑制可减轻肺部炎症和M.tb负荷，恢复GPX4表达，并增强巨噬细胞存活。我们的研究揭示了M.tb利用IDH-PPARγ轴诱导铁死亡并维持持续感染的机制，确定了通过破坏该相互作用治疗结核病的治疗靶点。
Abstract
Mycobacterium tuberculosis (M.tb) actively reprograms host lipid metabolism during infection; however, the underlying mechanism remains poorly understood. How M.tb manipulates macrophage lipid metabolism to induce lipid peroxidation and ferroptosis for bacterial persistence remains a fundamental question. Here, using single-cell RNA sequencing and proteomics, we show that M.tb infection substantially upregulates peroxisome proliferator-activated receptor gamma (PPARγ) in macrophages. Mechanistically, M.tb isocitrate dehydrogenase (IDH) interacts with PPARγ and impairs its proteasomal degradation. Elevated PPARγ suppresses glutathione peroxidase 4 (Gpx4) expression by recruiting the NCOR/SMRT corepressor complex to the Gpx4 promoter, resulting in increased lipid peroxidation and ferroptosis in infected macrophages. In mice, PPARγ knockout or pharmacological inhibition decreases lung inflammation and M.tb burden, restores GPX4 expression, and enhances macrophage survival. Our findings reveal a mechanism by which M.tb exploits the IDH-PPARγ axis to induce ferroptosis and sustain persistent infection, identifying therapeutic targets for tuberculosis treatment through disruption of this interaction.
如何引用
AMA
Wenyuan Pu, Ximeng Zhang, Man Tian, Zhiyi He, Jin Zhu, Shiyu Song, et al. Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection.. Nature communications. 2026; doi:10.1038/s41467-026-74032-w.
APA
Wenyuan Pu, Ximeng Zhang, Man Tian, Zhiyi He, Jin Zhu, Shiyu Song, et al (2026). Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection.. Nature communications. https://doi.org/10.1038/s41467-026-74032-w
GB/T 7714
Wenyuan Pu, Ximeng Zhang, Man Tian, Zhiyi He, Jin Zhu, Shiyu Song, et al. Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection.[J]. Nature communications, 2026 doi:10.1038/s41467-026-74032-w.
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