A Pseudomonas aeruginosa quorum-sensing metabolite manipulates macrophage ferroptosis through a methylation pathway

Tianyuan Jia (), Fengming Li, Tianzhen Li, Anmin Ren, Peiyi Lu, Yiling Liu, Yachun Zhou, Xiangke Duan, Yang Liu, Lin Zhong, Zhirong Zhang, Chris Soon Heng Tan () and Liang Yang ()
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Tianyuan Jia: The Second Affiliated Hospital of Southern University of Science and Technology
Fengming Li: Southern University of Science and Technology
Tianzhen Li: Southern University of Science and Technology
Anmin Ren: Southern University of Science and Technology
Peiyi Lu: Southern University of Science and Technology
Yiling Liu: Southern University of Science and Technology Hospital
Yachun Zhou: Southern University of Science and Technology
Xiangke Duan: The Second Affiliated Hospital of Southern University of Science and Technology
Yang Liu: Southern University of Science and Technology Hospital
Lin Zhong: The Second Affiliated Hospital of Southern University of Science and Technology
Zhirong Zhang: Southern University of Science and Technology
Chris Soon Heng Tan: Southern University of Science and Technology
Liang Yang: The Second Affiliated Hospital of Southern University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Ferroptosis is a type of iron- and lipid peroxidation–dependent programmed cell death that is involved in various diseases. Some pathogens manipulate host ferroptosis for pathogenesis; however, the potential mechanisms of action remain unclear. Pseudomonas aeruginosa is an opportunistic pathogen that relies on iron for its virulence, biofilm formation, and survival. Here, we report that P. aeruginosa employs the quorum-sensing metabolite, Pseudomonas quinolone signal (PQS), to induce ferroptosis in macrophages through a carnosine-N-methyltransferase (CNMT)-transferrin receptor 1 (TFR1) methylation pathway. Specifically, PQS promotes iron-dependent lipid peroxidation to induce ferroptosis in macrophages. Using high-resolution mass spectrometry–based cellular thermal shift assay (MS-CETSA)/thermal proteome profiling, we identify CNMT as the direct intracellular receptor of PQS in macrophages. Mechanistically, PQS binding increases the histidine methyltransferase (His MTase) activity of CNMT, catalysing methylation of TFR1 at His35. This methylation increases TFR1 protein production, resulting in amplified iron acquisition for ferroptosis. Crucially, the PQS–CNMT–TFR1 axis is distinct from canonical bacterial pathogens that exploit host cell death pathways, revealing the unique strategy of P. aeruginosa to exploit host epigenetic machinery.

Date: 2025
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DOI: 10.1038/s41467-025-65142-y

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