Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation
Abstract
Disulfidptosis is cell death caused by abnormal disulfide bonds, previously observed in cells with high SLC7A11 expression under glucose starvation. Whether other conditions can induce disulfidptosis remains unclear. However, we demonstrate that fumarate hydratase (FH)-deficient cells undergo disulfidptosis under glucose starvation. FH deficiency drives abnormal disulfide accumulation, promotes actin contraction, and consequently leads to cytoskeleton-plasma membrane dissociation. Under glucose starvation conditions, impaired oxidative tricarboxylic acid (TCA) cycle function in FH-deficient cells compromises NAD(P)H (the reduced forms of nicotinamide adenine dinucleotide and its phosphate) homeostasis, leading to redox system collapse. We find that targeting mitochondrial complex I enhances the reductive TCA cycle activity driving NADPH consumption while simultaneously suppressing the oxidative TCA cycle, thereby inducing disulfidptosis in the presence of glucose. Our findings establish a mechanistic link between FH deficiency and disulfidptosis, and define a therapeutically actionable vulnerability in FH-deficient tumors.
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BibTeX
@article{dou2026fumarate,
title = {{Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation}},
author = {Peng Dou and Xin Lu and Pengyu Geng and Yasemin Cole and Miao Bao and Xin Ge and Siming Pu and Lina Zhou and Xinyu Liu and Hang Li and Jinhui Zhao and Hang Gao and Fating Chen and Zhikun Lin and Ting Wang and Qi Li and Jianwen Hu and Jie Dai and Xu Qian and Zhengping Zhuang and Guowang Xu},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78274-6},
url = {https://www.nature.com/articles/s41467-026-78274-6},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation
AU - Peng Dou
AU - Xin Lu
AU - Pengyu Geng
AU - Yasemin Cole
AU - Miao Bao
AU - Xin Ge
AU - Siming Pu
AU - Lina Zhou
AU - Xinyu Liu
AU - Hang Li
AU - Jinhui Zhao
AU - Hang Gao
AU - Fating Chen
AU - Zhikun Lin
AU - Ting Wang
AU - Qi Li
AU - Jianwen Hu
AU - Jie Dai
AU - Xu Qian
AU - Zhengping Zhuang
AU - Guowang Xu
PY - 2026
DA - 2026/10/05
JO - Nature Communications
DO - 10.1038/s41467-026-78274-6
UR - https://www.nature.com/articles/s41467-026-78274-6
AB - Disulfidptosis is cell death caused by abnormal disulfide bonds, previously observed in cells with high SLC7A11 expression under glucose starvation. Whether other conditions can induce disulfidptosis remains unclear. However, we demonstrate that fumarate hydratase (FH)-deficient cells undergo disulfidptosis under glucose starvation. FH deficiency drives abnormal disulfide accumulation, promotes actin contraction, and consequently leads to cytoskeleton-plasma membrane dissociation. Under glucose starvation conditions, impaired oxidative tricarboxylic acid (TCA) cycle function in FH-deficient cells compromises NAD(P)H (the reduced forms of nicotinamide adenine dinucleotide and its phosphate) homeostasis, leading to redox system collapse. We find that targeting mitochondrial complex I enhances the reductive TCA cycle activity driving NADPH consumption while simultaneously suppressing the oxidative TCA cycle, thereby inducing disulfidptosis in the presence of glucose. Our findings establish a mechanistic link between FH deficiency and disulfidptosis, and define a therapeutically actionable vulnerability in FH-deficient tumors.
SN - 2041-1723
ER -