Intratumoral Fusobacterium nucleatum promotes ferroptosis resistance and a disulfide-stress-associated vulnerability under glucose restriction.
4 affiliations
- 1Department of Clinical Laboratory, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
- 2Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
- 3Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China.
- 4Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Abstract
Fusobacterium nucleatum (Fn) is an intracellular oncogenic bacterium implicated in multiple cancers. Although Fn has been linked to resistance to anticancer therapies, its effects on therapies targeting metabolic cell-death programs remain unclear. Here, we show that intratumoral Fn abundance is positively associated with SLC7A11 expression and that Fn infection attenuates Era- and RSL3-induced ferroptosis in tumor cells. Live-versus-killed, donor-based, and pharmacological evidence suggests that H₂S generated during Fn infection contributes to SLC7A11 induction and engagement of the downstream GSH/GPX4 axis. Fn infection also reduces lipid-peroxide and Fe²⁺ accumulation and is accompanied by ACSL4 downregulation and FTH1 upregulation. Fn-infected cells display increased glucose uptake and a heightened dependence on glucose. Under glucose-replete conditions, Fn-infected cells are relatively resistant to ferroptosis, whereas glucose deprivation exposes a conditional vulnerability accompanied by disulfide stress. RSL3 further sensitized Fn-infected cells to glucose restriction, and combined GPX4 inhibition with the GLUT1 inhibitor BAY876 enhanced antitumor activity in Fn-infected solid-tumor models. These findings identify a nutrient-dependent metabolic liability associated with Fn infection and support further evaluation of combined glucose-transport and GPX4 inhibition in appropriately controlled models.
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BibTeX
@article{li2026intratumoral,
title = {{Intratumoral Fusobacterium nucleatum promotes ferroptosis resistance and a disulfide-stress-associated vulnerability under glucose restriction.}},
author = {Yiqiu Li and Shuheng Dou and Shan Xing and Jiameng Hu and Xiaoyun Pan and Ziqi Yin and Ge Zhang and Songhe Guo},
journal = {Gut microbes},
year = {2026},
month = oct,
doi = {10.1080/19490976.2026.2748782},
url = {https://europepmc.org/article/MED/42911027},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Intratumoral Fusobacterium nucleatum promotes ferroptosis resistance and a disulfide-stress-associated vulnerability under glucose restriction.
AU - Yiqiu Li
AU - Shuheng Dou
AU - Shan Xing
AU - Jiameng Hu
AU - Xiaoyun Pan
AU - Ziqi Yin
AU - Ge Zhang
AU - Songhe Guo
PY - 2026
DA - 2026/10/22
JO - Gut microbes
DO - 10.1080/19490976.2026.2748782
UR - https://europepmc.org/article/MED/42911027
AB - Fusobacterium nucleatum (Fn) is an intracellular oncogenic bacterium implicated in multiple cancers. Although Fn has been linked to resistance to anticancer therapies, its effects on therapies targeting metabolic cell-death programs remain unclear. Here, we show that intratumoral Fn abundance is positively associated with SLC7A11 expression and that Fn infection attenuates Era- and RSL3-induced ferroptosis in tumor cells. Live-versus-killed, donor-based, and pharmacological evidence suggests that H₂S generated during Fn infection contributes to SLC7A11 induction and engagement of the downstream GSH/GPX4 axis. Fn infection also reduces lipid-peroxide and Fe²⁺ accumulation and is accompanied by ACSL4 downregulation and FTH1 upregulation. Fn-infected cells display increased glucose uptake and a heightened dependence on glucose. Under glucose-replete conditions, Fn-infected cells are relatively resistant to ferroptosis, whereas glucose deprivation exposes a conditional vulnerability accompanied by disulfide stress. RSL3 further sensitized Fn-infected cells to glucose restriction, and combined GPX4 inhibition with the GLUT1 inhibitor BAY876 enhanced antitumor activity in Fn-infected solid-tumor models. These findings identify a nutrient-dependent metabolic liability associated with Fn infection and support further evaluation of combined glucose-transport and GPX4 inhibition in appropriately controlled models.
SN - 1949-0976
SN - 1949-0984
ER -