Abstract
Pathogenic bacteria frequently manipulate host cell death pathways to facilitate infection, though the precise mechanisms remain elusive. Here, we demonstrate that pathogenic Escherichia coli disrupts copper homeostasis through upregulation of copper transporter CTR2, thereby triggering cuproptosis to drive infectious pathology. During infection, circulating lipopolysaccharide activates the morphological hallmarks of cuproptosis via the gut–LPS–liver axis. Furthermore, mitochondrial malate dehydrogenase 2 (MDH2) functions as a transcriptional regulator, triggering CTR2 expression and metabolic reprogramming via acetylation-dependent nuclear translocation in response to infection. Notably, inhibiting cuproptosis mitigates liver damage caused by infection, highlighting its critical role in pathogen-host interactions. These findings identify a mechanism underlying E. coli pathogenesis and support therapeutic approaches based on targeted modulation of metal-dependent cell death.
Acknowledgements
We extend our heartfelt gratitude to all contributors involved in this project. Special thanks are owed to Researcher Guolan Ma and Researcher Cong Li from the Kunming Institute of Zoology, Chinese Academy of Sciences, for their expertise in flow cytometry cell sorting and confocal microscopy imaging. Additionally, we sincerely thank Ms. Hongxu Yao from Yunnan Agricultural University for her invaluable contributions to data analysis and organization. We thank LetPub (www.letpub.com.cn) for linguistic assistance and pre-submission expert review.
Funding
This work was supported by the National Natural Science Foundation of China (Approval No. 32460868, 31960692 and 31660704), the Primate Laboratory Animal Biological Sample Resource Construction Project (Approval No. 2022YFF0710902), He Zhengming Laboratory Animal Expert Workstation of Yunnan (Kunming) (Approval No. YSZJGZZ-2022063) and He Zhengming of Yunnan Province Expert Workstation (Approval No. 202305AF150160) Project fund support for this study.
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Wang, H., Xiao, P., Chen, L. et al. Acetylated mitochondrial MDH2 regulates CTR2 transcription to induce cuproptosis during Escherichia coli infection. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73280-0
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DOI: https://doi.org/10.1038/s41467-026-73280-0
