Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal...

Clear cell renal cell carcinoma (ccRCC) exhibits a paradoxical fructose metabolism signature characterized by upregulation of the fructose transporter GLUT5 alongside downregulation of the catabolic enzymes (ketohexokinase, aldolase B, and triokinase), a pattern associated with poor prognosis. Functionally, unlike the pro-survival effect of fructose under glucose deprivation, in the presence of glucose, fructose co-treatment suppresses ccRCC cell proliferation, and induces profound mitochondrial dysfunction, including impaired oxidative phosphorylation, loss of membrane potential, excessive mitochondrial superoxide production, reduced mtDNA copy number, and downregulation of mitochondria-encoded electron transport chain subunits (notably ND2 and ND4 of complex I). Mechanistically, co-treatment with glucose and fructose creates a metabolic trap resulting in fructose-1-phosphate accumulation and ATP depletion. This energy crisis drives profound depletion of purine and pyrimidine nucleotide pools, which selectively triggers the PERK-eIF2S1-ATF4-CHOP axis of the integrated stress response, thereby mediating mitochondrial impairment and ultimately sensitizing ccRCC cells to intrinsic apoptosis via BID cleavage and caspase-3 activation under nutrient stress. Pharmacological treatment with the chemical chaperone 4-phenylbutyric acid (4-PBA) or nucleoside supplementation reverses mitochondrial dysfunction and fructose-induced cytotoxicity. The tumor-suppressive effect of fructose is validated in patient-derived organoids and xenograft mouse models, where fructose administration significantly attenuates tumor growth via ER stress. These findings reveal fructose-driven nucleotide depletion and PERK-dependent ER stress leading to mitochondrial dysfunction, which underlies the tumor-suppressive toxicity of fructose and exposes a targetable metabolic vulnerability in ccRCC.