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

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.