Glucose Deprivation-Mediated Disulfide Stress Induces Cell Death in FHdeficient Renal Cell Carcinoma

FH ^deficient renal cell carcinoma (RCC) is a highly metastatic and challenging malignancy. Here, we show that the aberrant accumulation of intracellular disulfides in FH ^deficient cells leads to actin cytoskeleton contraction and induces a caspase-independent form of cell death. However, inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) (which regulates actin cytoskeleton contraction) suppresses FH ^deficient cell death. Under glucose starvation, FH ^deficient cells attempt to mitigate NADPH consumption by downregulating the reductive tricarboxylic acid (TCA) cycle. However, defects in the oxidative TCA cycle prevent them from maintaining NADPH balance. Moreover, targeting mitochondrial complex I in FH ^deficient cells enhances the reductive TCA cycle while weakening the oxidative TCA cycle, thereby accelerating intracellular disulfide accumulation, tumor growth is significantly inhibited under low glucose conditions. Our study uncovers a caspase-independent cell death mechanism driven by disulfide stress and provides a potential therapeutic strategy targeting the metabolic vulnerability of FH ^deficient RCC.