Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection PMID: 42259813

ADC Targets in Oncology

2026-04-10

Mycobacterium tuberculosis IDH-PPARγ interaction suppresses GPX4 to drive macrophage ferroptosis and sustain persistent infection

Nat Commun. 2026 Jun 8. doi: 10.1038/s41467-026-74032-w.

Wenyuan Pu ^# ¹ ² , Ximeng Zhang ^# ³ , Man Tian ^# ¹ , Zhiyi He ^# ⁴ , Jin Zhu ⁵ , Shiyu Song ⁶ , Li Li ² , Panpan Lian ² , Renwei Lu ² , Ranran Wang ² , Kai Lin ² , Chaode Gu ² , Junaid Wazir ² , Caiyun Wang ¹ , Yixuan Sun ¹ , Jing Yang ³ , Yingwei Zhang ² , Huimei Chen ⁷ , Enrico Petretto ⁷ , Wangsen Cao ² , Rongrong Fan ⁸ , Eckardt Treuter ⁸ , Xia Zhang ⁹ , Nannan Liu ¹⁰ , Airong Yang ¹⁰ , Xinchun Chen ¹¹ , Hongwei Wang ¹² , Zhiqiang Huang ¹³

Affiliations

1. Department of Respiratory Medicine, Children's Hospital of Nanjing Medical University, Nanjing, P. R. China.
2. State Key Laboratory of Pharmaceutical Biotechnology, State Key Laboratory of Analytical Chemistry for Life Science, Department of Dermatology, Affiliated Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, Jiangsu Province, P. R. China.
3. Guangdong Provincial Key Laboratory of Infection Immunity & Inflammation, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, P. R. China.
4. Department of Respiratory Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P. R. China.
5. Huadong Medical Institute of Biotechniques, Nanjing, P. R. China.
6. Nanjing Lupine (YuShanDou) Biomedical Research Institute Co. Ltd., Nanjing, P. R. China.
7. Centre for Computational Biology, Duke-NUS Medical School, Outram, Singapore.
8. Department of Medicine Huddinge, Unit for Gastroenterology and Nutrition, Karolinska Institutet, Huddinge, Sweden.
9. Nanjing Public Health Clinical Center, the second hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, P. R. China.
10. Research Center for High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, P. R. China.
11. Guangdong Provincial Key Laboratory of Infection Immunity & Inflammation, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, P. R. China. [email protected].
12. State Key Laboratory of Pharmaceutical Biotechnology, State Key Laboratory of Analytical Chemistry for Life Science, Department of Dermatology, Affiliated Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, Jiangsu Province, P. R. China. [email protected].
13. State Key Laboratory of Pharmaceutical Biotechnology, State Key Laboratory of Analytical Chemistry for Life Science, Department of Dermatology, Affiliated Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, Jiangsu Province, P. R. China. [email protected].
# Contributed equally.

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.