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Peer-reviewedCC BYCell Metabolism

IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition

  • Siavash Mansouri1
  • Golnaz Hesami1
  • Anoop Ambikan2
  • Annika Karger1
  • Stephan Klatt3
  • Ujjwal Neogi2
  • Kondababu Kurakula4
  • Blerina Aliraj5
  • Anne Miller6
  • Boryana Petrova7
  • Miloslav Šanda8
  • Evelyn Sirait‐Fischer9
15 more authors
  • Stefan Guenther (5992991)10
  • Carsten Tobias Kuenne10
  • Clemens Ruppert11
  • Ibrahim Alkoudmani12
  • Stefan Gattenlöhner13
  • Sven Zukunft3
  • Ingrid Fleming3
  • Arvand Haschemi14
  • Thorsten Stiewe15
  • Friedrich Grimminger16
  • Martin Reck17
  • Andreas Weigert9
  • Werner Seeger18
  • Soni Savai Pullamsetti
  • Rajkumar Savai
18 affiliations
  1. 1Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-pulmonary Institute (CPI), Bad Nauheim, Germany
  2. 2The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
  3. 3Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany
  4. 4Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Free University Medical Center, Amsterdam, the Netherlands
  5. 5Goethe University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Frankfurt, Germany
  6. 6Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
  7. 7Department of Core Facilities, Medical University of Vienna, Vienna, Austria
  8. 8Max Planck Institute for Heart and Lung Research, DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany; Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
  9. 9Goethe University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Frankfurt, Germany; Department for Immunity of Inflammation, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  10. 10Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-pulmonary Institute (CPI), Bad Nauheim, Germany
  11. 11Department of Internal Medicine, DZL, CPI, Justus Liebig University, Giessen, Germany
  12. 12Department of General and Thoracic Surgery University Hospital Giessen, Giessen, Germany
  13. 13Department of Pathology, Justus Liebig University, Giessen, Germany
  14. 14Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
  15. 15Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Institute of Molecular Oncology, Philipps-University, Marburg, Germany
  16. 16Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Department of Internal Medicine, DZL, CPI, Justus Liebig University, Giessen, Germany
  17. 17Department of Thoracic Oncology, Airway Research Center North, DZL, Lungen Clinic, Grosshansdorf, Germany
  18. 18Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-pulmonary Institute (CPI), Bad Nauheim, Germany; Department of Internal Medicine, DZL, CPI, Justus Liebig University, Giessen, Germany
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Abstract

Tumor-associated macrophages (TAMs) possess both tumor-promoting and tumor-inhibiting roles. Here, we explore TAMs' anti-tumor functions, focusing on the immune responsive gene 1 (IRG1) and its product, itaconate, in lung cancer development. Spatial metabolomics reveals that endogenous itaconate is markedly depleted within lung tumor regions compared with adjacent non-tumor tissue. Single-cell RNA sequencing shows that macrophages are the primary cells expressing IRG1 in human and mouse lung tumors. Both IRG1 knockout and transplantation of IRG1-depleted bone marrow leads to increased lung tumor growth in various mouse lung tumor models. Additionally, 4-octyl itaconate (Octyl Ita) reduces tumor growth in vitro, in vivo, and in ex vivo human tumor precision-cut lung slices. An integrated multi-omics analysis shows that IRG1/itaconate causes a metabolic shift in cancer cell and pro-tumor macrophages, mainly by inhibiting the pentose phosphate pathway (PPP) through targeting glucose-6-phosphate dehydrogenase (G6PD) activity, thereby suppressing cancer cell growth and transforming pro-tumor macrophages into anti-tumor macrophages. Thus, leveraging IRG1/itaconate's tumor-suppressive effects or using Octyl Ita could be a novel lung cancer therapy.

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Cite

BibTeXRIS
BibTeX
@article{mansouri2026irg1itaconate,
  title = {{IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition}},
  author = {Siavash Mansouri and Golnaz Hesami and Anoop Ambikan and Annika Karger and Stephan Klatt and Ujjwal Neogi and Kondababu Kurakula and Blerina Aliraj and Anne Miller and Boryana Petrova and Miloslav Šanda and Evelyn Sirait‐Fischer and Stefan Guenther (5992991) and Carsten Tobias Kuenne and Clemens Ruppert and Ibrahim Alkoudmani and Stefan Gattenlöhner and Sven Zukunft and Ingrid Fleming and Arvand Haschemi and Thorsten Stiewe and Friedrich Grimminger and Martin Reck and Andreas Weigert and Werner Seeger and Soni Savai Pullamsetti and Rajkumar Savai},
  journal = {Cell Metabolism},
  year = {2026},
  month = jun,
  doi = {10.1016/j.cmet.2026.05.005},
  url = {https://doi.org/10.1016/j.cmet.2026.05.005},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition
AU  - Siavash Mansouri
AU  - Golnaz Hesami
AU  - Anoop Ambikan
AU  - Annika Karger
AU  - Stephan Klatt
AU  - Ujjwal Neogi
AU  - Kondababu Kurakula
AU  - Blerina Aliraj
AU  - Anne Miller
AU  - Boryana Petrova
AU  - Miloslav Šanda
AU  - Evelyn Sirait‐Fischer
AU  - Stefan Guenther (5992991)
AU  - Carsten Tobias Kuenne
AU  - Clemens Ruppert
AU  - Ibrahim Alkoudmani
AU  - Stefan Gattenlöhner
AU  - Sven Zukunft
AU  - Ingrid Fleming
AU  - Arvand Haschemi
AU  - Thorsten Stiewe
AU  - Friedrich Grimminger
AU  - Martin Reck
AU  - Andreas Weigert
AU  - Werner Seeger
AU  - Soni Savai Pullamsetti
AU  - Rajkumar Savai
PY  - 2026
DA  - 2026/06/03
JO  - Cell Metabolism
DO  - 10.1016/j.cmet.2026.05.005
UR  - https://doi.org/10.1016/j.cmet.2026.05.005
AB  - Tumor-associated macrophages (TAMs) possess both tumor-promoting and tumor-inhibiting roles. Here, we explore TAMs' anti-tumor functions, focusing on the immune responsive gene 1 (IRG1) and its product, itaconate, in lung cancer development. Spatial metabolomics reveals that endogenous itaconate is markedly depleted within lung tumor regions compared with adjacent non-tumor tissue. Single-cell RNA sequencing shows that macrophages are the primary cells expressing IRG1 in human and mouse lung tumors. Both IRG1 knockout and transplantation of IRG1-depleted bone marrow leads to increased lung tumor growth in various mouse lung tumor models. Additionally, 4-octyl itaconate (Octyl Ita) reduces tumor growth in vitro, in vivo, and in ex vivo human tumor precision-cut lung slices. An integrated multi-omics analysis shows that IRG1/itaconate causes a metabolic shift in cancer cell and pro-tumor macrophages, mainly by inhibiting the pentose phosphate pathway (PPP) through targeting glucose-6-phosphate dehydrogenase (G6PD) activity, thereby suppressing cancer cell growth and transforming pro-tumor macrophages into anti-tumor macrophages. Thus, leveraging IRG1/itaconate's tumor-suppressive effects or using Octyl Ita could be a novel lung cancer therapy.
SN  - 1550-4131
SN  - 1932-7420
ER  -