SIRT3–IDH2 axis is a target of dietary fructose: implication of IDH2 as a key player in dietary carcinogen toxicity in mice colon

Recent epidemiological studies have shown that dietary fructose intake is associated with an increased risk of colorectal cancer, yet its specific molecular mechanisms in colon carcinogenesis remain underexplored. Here we investigate the molecular mechanisms by which dietary fructose contributes to colon carcinogenesis, focusing on the role of mitochondrial NADP⁺-dependent isocitrate dehydrogenase 2 (IDH2). Using an unbiased multiomics approach (transcriptomics and proteomics), liver and colon tissues from fructose-fed wild-type mice were analyzed to identify key genes involved in cancer-related pathways. In addition, human liver transcriptomic data (GSE256398) were analyzed to confirm alterations in aryl hydrocarbon receptor (AhR) signaling and the sirtuin (SIRT)3-IDH2 axis. IDH2-knockout mice were exposed to a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), to validate IDH2's role in colon cancer development. In vitro, fructose's effects on SIRT3 expression and IDH2 activity were assessed. Fructose-fed wild-type mice exhibited suppressed AhR signaling, increased oxidative stress and mitochondrial dysfunction via the SIRT3-IDH2 axis. In human liver datasets, AhR-associated genes and SIRT3-IDH2 expression were reduced in metabolic dysfunction-associated steatotic liver disease and cirrhosis. The IDH2-knockout mice showed heightened DNA damage, colonic tumorigenesis and mitochondrial and glutathione-mediated detoxification disruptions following PhIP exposure. In vitro, fructose reduced SIRT3 expression and IDH2 activity, further supporting its role in promoting colon carcinogenesis. Fructose promotes colon carcinogenesis by disrupting mitochondrial function and impairing DNA damage response mechanisms, particularly through SIRT3-IDH2 axis suppression. These findings highlight the critical role of mitochondrial dysfunction in fructose-induced carcinogenesis and suggest the SIRT3-IDH2 axis as a potential therapeutic target.