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.
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Acknowledgements
We are grateful for the kind support from all members of Prof. Wang’s team. We thank Professor Zhe Wang (Shanghai Jiao Tong University) for providing the antibody against M.tb GROEL1.
Funding
This work was supported by the National Key Research and Development Program of China (Grant 2022YFF0710801 to H.W.); the National Natural Science Foundation of China (Grants 82571040 to Z.H., 82370899 to H.W., 82070912 to H.W., 825B2024 to R.W.); the Fundamental Research Funds for the Central Universities (Grants 14380538 to Z.H. and 14380550 to Z.H.); State Key Laboratory of Analytical Chemistry for Life Science (Grants 5431ZZXM2615 and 5431ZZXM2404 to H.W.); Visiting Researcher Fund Program of State Key Laboratory of Metabolism and Regulation in Complex Organisms (Grant KF20250005 to Z.H.); the Natural Science Foundation of Jiangsu Province (Grant BK20251988 to Z.H., BK20251803 to H.W.); the NUS-NJU Research Collaboration Fund (Grants 14915200 to H.W., 2025-NJUNUS-0001 to E.P.); the Fundamental Research Funds for the Central Universities and Nanjing University International Collaboration Initiative (Grant 14380549 to H.W.); the Young Talent Development Promotion Association of Nanjing University (2026 to Z.H.); the Team Building and Start-up Funds of Nanjing University (Grant 14912217 to Z.H.); and the Nanjing University Laboratory Safety Research Project (Grant LSK202402 to Z.H.). This work was also supported by the Swedish Cancer Society (Grants 232891Pj to R.F., 211582Pj to E.T., and 243547Pj to E.T.); the Swedish Research Council (Grants 2023-02311 to R.F. and 2022-00545 to E.T.); the EFSD Novo Nordisk Future Leaders Award (to R.F.); the Novo Nordisk Foundation (Grant NNF23OC0084552 to E.T.); the Karolinska Institute Strategic Research Programme in Diabetes (SRP) Rolf Luft Grants (to R.F.); the Jiangsu Funding Program for Excellent Postdoctoral Talent (Grant 2025ZB871 to W.P.) and the National Medical Research Council of Singapore (Grant MOH-OFIRG24jan-0010 to E.P.).
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Pu, W., Zhang, X., Tian, M. et al. Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection. Nat Commun (2026). https://doi.org/10.1038/s41467-026-74032-w
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DOI: https://doi.org/10.1038/s41467-026-74032-w
