Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation.

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.