Dietary Fructose Suppresses Hepatocellular Carcinogenesis through Fructose 1-Phosphate-Mediated Inhibition of Mannose Phosphate Isomerase

Fructose consumption increases risks of obesity-related metabolic diseases and some cancers, but remains controversial in hepatocellular carcinoma (HCC) ¹ . Animal studies suggest high fructose promotes HCC ^2,3 , whereas human studies found an inverse correlation between fructose intake and risk of live cancer ⁴ . Moreover, fructose metabolism is significantly suppressed in HCC, including loss of fructose-1,6-bisphosphate aldolase B (ALDOB) ^5-7 . Here we show that dietary fructose suppresses HCC through fructose 1-phosphate (F1P)-mediated inhibition of mannose phosphate isomerase (MPI). We performed single-cell transcriptomics and identified subsets of cancer cells with fructose catabolic capability in human HCC tissues, termed fructophilic hepatoma cells (fp-HCs, SLC2A2 ^high KHK ^high ALDOB ^low ), featuring relatively high expressions of SLC2A2 and ketohexokinase ( KHK ) but low ALDOB expression. Fructose-derived F1P inhibits HCC by remodeling glucose and mannose metabolism in HCC mouse models with aldob liver-specific knockout mice. Mechanistically, F1P competitively binds to and inhibits MPI, reducing protein N-glycosylation and triggering maladaptive ER stress and dilation, ultimately impairing cell viability. Furthermore, we identified Ebselen as a potent MPI inhibitor through screening FDA-approved drugs and validated the efficacy in mouse models. Together, our study reveals a novel mechanism by which dietary fructose inhibits HCC through metabolic rewiring of glucose and mannose, offering a therapeutic strategy to target cancer metabolic vulnerabilities.